Cancer Treatment Diet

10 Ways To Fight Off Cancer

10 Ways To Fight Off Cancer

Learning About 10 Ways Fight Off Cancer Can Have Amazing Benefits For Your Life The Best Tips On How To Keep This Killer At Bay Discovering that you or a loved one has cancer can be utterly terrifying. All the same, once you comprehend the causes of cancer and learn how to reverse those causes, you or your loved one may have more than a fighting chance of beating out cancer.

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50 Things About 50 Cancers

This ebook from medical practitioner and family doctor Dr. Parajuli gives you all of the signs and symptoms that you need to know in order to catch cancer in the very early stages and protect yourself from it. You don't have to worry about if you have cancer anymore, and better yet you don't have to spend thousands of dollars to make sure of that either! All it takes is a bit of knowledge and you are on your way! This book also teaches about other aspects of cancer patients, such as how to live with different kinds of cancer, how to prepare yourself mentally to accept this reality if it IS a reality for you, and how to deal with doctors and insurance companies. This book is easy to read and in PDF format, so you don't have to worry at all about reading it. Make it easy on yourself!

Do I Have Cancer Overview

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Gastrointestinal Cancer

Department of Gastrointestinal Medicine and Nutrition The University of Texas M. D. Anderson Cancer Center Houston, TX 77030-4009 USA Oncology The University of Texas M. D. Anderson Cancer Center Houston, TX 77030-4009 USA Oncology The University of Texas M. D. Anderson Cancer Center Houston, TX 77030-4009 USA Oncology The University of Texas M. D. Anderson Cancer Center Houston, TX 77030-4009 USA M. D. Anderson Cancer Center Houston, TX 77030-4009 USA Gastronomical i.e. gastrointestinal cancer edited by Jaffer A. Ajani et al. . p. cm. (M.D. Anderson cancer care series) ISBN 0-387-22090-9 (sc alk. paper) 1. Digestive organs Cancer. I. Title Gastronomical cancer. II. Title Gastrointestinal cancer. III. Ajani, Jaffer A. IV. Series.

Cancer Drug Discovery and Development

Proteasome Inhibitors in Cancer Therapy, edited by Julian Adams, 2004 Nucleic Acid Theapeutics in Cancer, edited by Alan M. Gewirtz, 2004 Cancer Chemoprevention, Volume 1 Promising Cancer Chemopreventive Agents, edited by Gary J. Kelloff, Ernest T. Hawk, and Caroline C. Sigman, 2004 DNA Repair in Cancer Therapy, edited by Lawrence C. Panasci and Moulay A. Alaoui-Jamali, 2004 edited by George Morstyn, MaryAnn Foote, and Graham J. Lieschke, 2004 Handbook of Anticancer Pharmacokinetics and Pharmacodynamics, edited by William D. Figg and Howard L. McLeod, 2004 Anticancer Drug Development Guide Preclinical Screening, Clinical Trials, and Approval, Second Edition, edited by Beverly A. Teicher and Paul A. Andrews, 2004 Handbook of Cancer Vaccines, edited by Michael A. Morse, Timothy M. Clay, and Kim H. Lyerly, 2004 Drug Delivery Systems in Cancer Therapy, edited by Dennis M. Brown, 2003 Oncogene-Directed Therapies, edited by Janusz Rak, 2003 Cell Cycle Inhibitors in Cancer Therapy Current...

Adenovector Mediated Cancer Gene Therapy

Early-region (E1)-deleted, replication-defective adenovectors have been widely used in preclinical and clinical studies of cancer gene therapy. Recently, the use of conditional replicating or oncolytic adenovectors in cancer gene therapy or virotherapy has received much attention. Clinical trials with E1-deleted adenovectors and oncolytic adenovirus have shown that adenovector-mediated cancer gene therapy is well tolerated and can produce clinical responses in patients with advanced diseases. Moreover, numerous strategies to improve vector safety and therapeutic efficacy have been explored, including vector modification and the development of vector formulations to enhance transduction efficiency, to modulate tropism for vector targeting, to improve controlled or tissue-specific transgene expression, and to reduce vector-related toxicity. Yet, much has to be improved in this type of vector system to ensure its future success in clinical applications.

Hormonal Carcinogenesis

It was Furth9 who first tentatively suggested that hormones might be directly carcinogenic not by a genotoxic mechanism per se but by influencing the rate of cell division and thereby increasing the potential for spontaneous mutations. Drawing partially on the work of others, he suggested that while DNA molecules replicate, some copying mistakes might go unrepaired. In fact, the chromosomal instability at mitosis, could produce cells carrying new karyotypes, which are potential ancestors of novel clones liable to become malignant tumors.9 Furth9 went on to describe five lines of evidence to support the hypothesis of carcinogenesis without an extrinsic, genotoxic carcinogen. This evidence drew heavily on his own experience with thyroid carcinogenesis in the rat. During the early 1970s, MacMahon and col-leagues10 published a series of papers suggesting that estrogens, generally, and estradiol, specifically, could be involved in human breast cancer carcinogenesis. At the same time, there...

Current Trends In Hormonerelated Cancers

While we propose that genetic variation influences cancer risk in hormone-responsive tissue by programming endogenous hormone production, transport, and response, other lifestyle, diagnostic, and treatment factors appear to explain short-term trends in incidence and mortality. For example, trends in hormone-related cancers, such as breast, ovarian, prostate, and uterine cancers, show that incidence and mortality rates are influenced by several factors, including changing patterns of hormone-replacement therapy, oral contraceptive use, disease-screening practices, reproductive characteristics, and other lifestyle factors that vary over time and by racial ethnic group. During the past two decades, efforts to diagnose early stage cancer through screening have resulted in artificial increases in breast and prostate cancer incidence. The impact of changing reproductive factors and screening efforts on the incidence and mortality of each of these hormone-associated cancers is discussed...

Hormones Centrosomes and Genomic Instability in Mammary Carcinogenesis

The centrosome duplication cycle, like the cell cycle, is regulated by a vital system of checkpoint-signaling proteins, about which little is currently known. Errors in centrosome duplication and or distribution can result in aberrant daughter cells that either lack centrosomes (acentric cells) or receive a single centrosome, producing mono-polar spindles, or they can receive more than two centrosomes, resulting in the assembly of multipolar spindles during mitosis. These aberrations can lead to catastrophic errors in chromosome distribution resulting either in cell death or transformation to become tumor cells. Using antibodies specific for centrosome associated proteins, we and others have noted that many tumors, both in-vitro and in-vivo, display cells with a variety of centrosome aberrations (1-7). The most commonly reported defect causes cells to develop supernumerary centrosomes (greater than the expected 1-2 centrosomes cell), a process identified as centrosome amplification....

Chromosomal abnormalities in cancer

The abnormal nature of chromosomes of cancer cells was recognised many years ago, but the potential significance of chromosomal aberrations was realised only after the discovery by Nowell and Hungerford (I960) of the Philadelphia chromosome in patients with chronic myeloid leukaemia. The virtual invariability of the association of this abnormal chromosome with a form of human cancer served to emphasise the significance of chromosomal aberrations in the pathogenesis of cancer. The importance of cytogenetics as a major discipline of cancer biology has been strengthened by the non-random nature of chromosomal changes. Most of the abnormalities are restricted to a few sites of the human genome (Heim and Mitelman, 1987). Sutherland (1979) showed the presence of non-staining gaps in both chromatids, which are inherited in a Mendelian fashion. These have been called the fragile sites. These fragile sites appear to be the major targets of mutagens and carcinogens (Yunis et al., 1987). In some...

The Molecular Pathogenesis of Human Prostate Cancer

Prostate cancer (PCA) has become the most commonly diagnosed cancer among men in the USA, with an estimated 189,000 cases diagnosed in 2002 (1). Encouragingly, over the past several years, increased use of serum prostate-specific antigen (PSA) screening has increased the fraction of men diagnosed with PCA confined to the prostate gland, leading to more effective use of surgery and radiation therapy for treatment, and to a decline in PCA mortality (2, 3). Despite these improvements, some 30,200 men will likely died of progressive metastatic cancer in 2002 (1). Furthermore, even though men with early PCA can be cured using surgery or radiation therapy, the side effects of treatment frequently include erectile dysfunction, urinary incontinence, or rectal irritation (4-6). New insights into the etiology of PCA are needed so that new strategies for its prevention can be developed. Recent studies of the earliest molecular steps in the development of human PCA have generated new evidence...

Factors Affecting Efficacy Of Ad As An Anticancer Agent

Initial attempts to utilize Ads as anticancer therapeutics were undertaken shortly after their discovery in early 1950s (4). Administration of wild-type Ads into patients with cervical carcinomas did not demonstrate significant efficacy. As a result, further development of Ad-based anticancer therapeutics was essentially abandoned for four decades. By the mid-1990s, accumulated data on the virus genome organization and protein expression coupled with significant insights into mechanisms governing Ad-host cell interactions revived the idea of using Ad for the therapy of cancer in humans resulting primarily from the following three remarkable features of the virus (1) its great efficiency in killing infected cells during virus replication, (2) it's ability to infect a variety of primary human cells in vitro, and (3) it's relative safety and ease of propagation and large-scale production in the laboratory. A number of academic research teams and companies worldwide have focused their...

The Role Of Leukemia Inhibitory Factor In Cancer And Cancer Metastasis

Department of Bioimmunotherapy, The University of Texas, M. D. Anderson Cancer Center, Houston, Texas, U.S.A Key words Leukemia inhibitory factor (LIF), Cancer, Metastasis Abstract Leukemia inhibitory factor (LIF) is a cytokine that exerts pleiotropic activities. LIF is a member of the interleukin-6 family of cytokines which share a similar receptor complex and signal through the gp 130 receptor subunit. Several neoplastic cells originating from various tissues express either LIF, its receptor, or both and respond to this cytokine. Data accumulated thus far provide a complex picture of LIF activities with LIF being stimulatory, inhibitory or having no effect, depending on the system in which it is studied. LIF appears to play an important role in stimulating the growth of certain tumours, and in affecting the surrounding tissue and the target organ of tumour metastases, particularly bone and skeletal tissue. Overproduction of LIF is likely to have significant constitutional effects....

Urogenital Conditions Associated With Testicular Cancer

Cryptorchidism is a common congenital disorder in which one or both testicles fail to descend into the scrotum before birth. Over half of the boys who are born with cryptorchidism experience spontaneous testicular descent during the first year of life. A history of persistent cryptorchidism, in which spontaneous descent does not occur, is the major established risk factor for testicular cancer. Epidemiologic studies consistently find associations between a personal history of cryptorchidism and risk of testicular cancer, and reported estimates of relative risk range from 2.5 to 18.1 5 11 42-60 Some studies found cryp-torchidism to be more strongly associated with seminoma than with other histologic types. The specific mechanisms whereby a history of cryptorchidism predisposes an individual to testicu-lar cancer are not known although two general scenarios have been postulated. The abdominal-location hypothesis asserts that pathogenic effects of the suprascrotal position are...

The Role of Progesterone in the Etiology of Breast Cancer

While E's role in the etiology of BC has been extensively studied, and E has been shown to play multiple roles in BC pathways, less is known about the relationship between P and BC etiology. Initially, P was thought to protect the breast from cancer based on its anti-proliferative effects on the endometrium. However, several recent studies suggest that P is involved in multiple pathways associated with BC. In 1994, Shi, et al. (39) summarized evidence documenting the role of P in the initiation and promotion of BC, including how P 1. Stimulates growth in the normal human breast (in contrast to its effect on the endometrium). 2. Has mitogenic effects on BC cell lines. 3. Promotes mammary tumor growth in rodents. 4. Induces mitogenic growth factors and their receptors in hormone receptor positive BC cells. 5. Regulates receptors for adhesion molecules involved in metastases. 6. Tumorigenesis is inhibited by anti-progestins. Details regarding this evidence and more recent work...

DNA methylation and cancer

In vertebrate somatic cells, epigenetic regulation of gene expression reinforces stable expression states at different loci. These ''expression states'' are associated with particular molecular signatures of DNA and chromatin modifications that are characteristic of active or repressed genes. The end result is that differentiated cells have a restricted transcriptome profile and a limited developmental potential. In cancer cells, this regulatory mechanism is altered such that the transcriptome profile is changed to one that promotes cancer progression and maintenance. In cell lines, selection for rapid cell division can impose further epigenetic changes. In general, cancer cells possess aberrant patterns of hypomethylation at repeat sequences and hypermethylation at the promoters of many genes (Baylin and Herman, 2000 Bjornsson et a ., 2004 Feinberg et a ., 2002 Feinberg and Tycko, 2004 Jones and Laird, 1999). This process can give the cell a selective growth advantage akin to...

Use of Human Breast Cancer Cell Lines to Detect Specific Receptor Induced Proteins

Before the development of DNA micro-array and SAGE approaches, the use of labelling of proteins synthesized in cell culture, before and after hormone stimulation, allowed us detection of several steroid hormone specific induced proteins, as defined by their molecular weight in SDS-PAGE, which could then be identified and studied in tumour samples to specify their significance in human carcinogenesis (16). Regarding progestins, using dose response curves and anti-hormones, we could not discriminate between MPA and R5020 (promegestone) with respect to the induction of specific PR responses, such as the secreted 48 kD protein (16-17) and the cellular 250 kD protein, which were both inhibited by the anti-progestin RU486, but not by the anti-androgen flutamide (18 and D.Chalbos et unpublished).

Microsatellite instability in cancer progression

The mutator phenotype and cancer The progression of cancer to the metastatic stage is identifiable, as the above discussion implies, with genomic instability. This conceivably could lead to genetic alterations, primary as well as cumulative secondary changes, that might confer selective proliferative advantage on variants generated by this genomic flux. Therefore, clonal expansion of these variants may be considered to be a major force in tumour progression. The rate of generation of metastatic variants and the rate of spontaneous mutation of drug-resistant variants in tumours are several orders of magnitude greater than the rate of background mutations. Loeb (1991,1994) therefore proposed the concept of the mutator phenotype in order to account for the high mutation rates occurring in cancer. This concept is based on the inherent instability associated with microsatellite loci occurring in the genome. Microsatellites are repetitive nucleotide sequences of varying lengths which occur...

What Is Hereditary Breast Cancer

It is worth stating at the outset that the term hereditary breast cancer, while in widespread usage, is somewhat problematic. Hereditary implies that the propensity to disease in that individual has been inherited. Thus, the implication is that breast cancer can be dichotomized into those cases where susceptibility is inherited and those where it is not. This concept arose from consideration of cancers with a simpler genetic basis such as retinoblastoma and Wilm's tumor, which can be usefully categorized in this way (2,3). As we shall see, the situation is much more complex for breast cancer. There are many different susceptibility genes for breast cancer, and a substantial fraction (in fact the majority) of breast cancer cases occur in women who are predisposed in some way. It is also worth emphasizing here that there is no known pathologically distinct type of breast cancer that is hereditary (although certain pathological features are more common in BRCA1 carriers), so it is not...

Telomerase function genetic instability cell proliferation and cancer metastasis

Telomeric diminution is a consequence of replication ineffeciency known as the end replication problem. DNA is synthesised by conventional DNA polymerases unidirectionally with a 5'-3' polarity and this requires an RNA primer and the lagging strand cannot be completed. This leaves a gap at the 5' end of the lagging strand (Watson, 1972 see also Olovnikov, 1996 Villeponteau, 1996). Failure to fill this gap results in a progressive loss of DNA and a consequent shortening of the chromosome. This loss has been postulated to be the reason why the replicative life of a cell is limited (Harley et al., 1990). An enzyme called telomerase has been identified in Tetrahymena thermophila (Greider and Blackburn, 1987). This enzyme solves the end-replication problem by adding repetitive telomeric sequences and maintains the integrity of the telomere. The telomerase is a ribonucleoprotein with an RNA component encoded by a single gene (Feng et al., 1995) and two proteins of 80 and 95 kDa (Collins et...

What is the Significance of FAS Overexpression in Cancer Cells

Is FAS over-expression a marker only associated with aggressive solid tumours or is it actively engaged in mammary carcinogenesis FAS activity and endogenous fatty acid synthesis are required for normal embryonic development since FAS gene knock-out is lethal in mice (43). In normal adult cells, except in lactating mammary glands (30), FAS activity is low since fatty acids are mostly provided by food and imported from local vascularization (47). We hypothesize that in solid tumours the bio-availability of fatty acids from the circulation is weak because their vascularization is generally poor, as also indicated by the lower extra-cellular pH. BC cells overexpressing FAS may have a growth advantage compared to normal peripheral cells in these solid tumours. Cancer cells require nutrients to grow, and not only mitogens. In addition to proteins, they also need fatty acids as precursors for synthesis of membranes, lipid mediators and lipid anchors and they may use FAS for endogenous...

Epidemiological Studies Of Familial Breast Cancer

Much of the impetus for breast cancer genetics has come from observations of families with extraordinary numbers of cases of the disease (5). These families have often been critical to the identification of the high-risk susceptibility genes. They are, however, less useful for evaluating the risks associated with a family history of breast cancer or with any particular gene, because they are not collected in a systematic fashion. To provide useful information for genetic counseling, risk estimates from epidemiological studies are required. Fortunately, many such studies have been conducted. Most are case-control studies that compare the family history of breast cancer in cases with the family history in controls. Other studies are cohort studies of relatives of breast cancer patients. These latter studies include those based on record linkage with national records, notably those done in Sweden, Iceland, and Utah, and they provide estimates that are free from any potential recall bias...

Twin Studies and Bilateral Breast Cancer

In principle, the familial aggregation of breast cancer may be due either to genetic factors or to lifestyle or environmental factors that are shared among relatives. The latter possibility is unlikely in that no lifestyle risk factors that are sufficiently strong to materially affect familial aggregation of the disease have been identified. More formal evidence that familial aggregation has a genetic basis comes from twin studies. Based on an analysis of population-based twin registers from the Nordic studies, Lichtenstein et al. (23) found that the risk of breast cancer in the monozygotic (MZ) twins of cases was about twice as great as the risk in the dizygotic (DZ) twins. Using a particular multifactorial model, this study estimated that about 27 of the variation in breast cancer risk was genetic. This particular estimate should be viewed cautiously since it does depend on the model used and on how one defines the variation in breast cancer risk, but it does point to a substantial...

Genetic Alterations of Colorectal Cancer

The molecular genetic alterations in colorectal carcinoma are among the best understood in human cancer and involve abnormalities in multiple dominant-acting oncogenes and tumor-suppressor genes (Kinzler and Vogelstein, 1996 Fearon and Dang, 1999). Various pathways of colorectal carcinogenesis are evident in sporadic, familial, and inflammatory bowel disease-associated neoplasms. The somatic alterations in sporadic colo-

Breast Cancer Susceptibility And Other Risk Factors

An important and largely unresolved question is the relationship between genetic and lifestyle risk factors for breast cancer. The combined analysis by the Collaborative Group examined the effect of several important risk factors on the familial risk of breast cancer, including parity, age at first full-term pregnancy, and ages at menarche and menopause. In each case, they found that the relative risks conferred by these risk factors were similar in women with and without a family history (1). These results imply that such risk factors can be assumed to multiply the familial risks of breast cancer (an assumption made in the Tyrer et al. and Gail models). It also suggests that such risk factors are largely independent of genotype. Whether this is true for specific susceptibility genes, in particular BRCA1 and BRCA2, is less clear however. Several studies have examined the effects of these risk factors in BRCA1 2 carriers but many of the results are contradictory, perhaps reflecting...

Models Of Breast Cancer Susceptibility

Several models have been developed to derive estimates of risk to women with a family history of breast cancer or to estimate the probability of carrying a mutation in the BRCA1 or BRCA2 gene. These models can be broadly categorized as empirical models and genetic models. Empirical models are based summarily on measures of family history, such as the number of affected relatives and other risk factors. Perhaps the most widely used model of this kind is the Gail model, which incorporates a variety of breast cancer risk factors in addition to the number of affected relatives (31). Such a model is useful in the general population context, for example, in selecting women for prevention trials but is less useful in high-risk families where the nuances of the family history cannot be captured well. Genetic models seek to model the familial aggregation of the disease in terms of the effects of specific genes or other familial risk factors. These models are developed from population-based...

The Qualitative Burden Of Cancer Survivorship From The Patients Perspective

To better understand the magnitude of the qualitative burden of cancer from the patient's perspective, the LAF conducted an open invitation Internet-based survey posted on the LAF Web site (http www.laf.org). The survey was a large-scale battery of 83 queries about pathological and psychosocial topics such as medical support, emotional support, patient attitude, secondary health problems, financial issues, social relations, employment problems, and concerns about activities of daily living. From October 1-6, 2004, 1024 self-identified cancer patients responded and completed the survey. Demographics of the responders (shown in Table 1) indicated that most were Caucasian, married, college graduates, and living in or near a city. Ninety percent of responders had medical insurance and 57 had annual income greater than 50,000. Most of the responders were remote from cancer therapy with 73 more than 2 years from diagnosis and 45 as long-term survivors more than 5 years from diagnosis. Only...

ProgesteronePR Signaling in Mammary Carcinogenesis

In normal mammary epithelial cells, the initial impact of progesterone signaling through PR results in an increase in proliferation. Therefore, in its capacity as a mammary gland mitogen, progesterone has the potential to trigger carcinogenesis. An excellent example of this P action is the animal model developed by Lanari et al. in which the progestin, medroxyprogesterone induces mammary tumors (21). Another example is the p53-null mutant mammary epithelium in which progesterone alone strongly enhances mammary tumorigenesis (22). Studies from our laboratory (as reviewed here) showed that a deregulation in progesterone action (as in PR-A transgenics) can alter the growth potential of epithelial cells, at least, in part, at the level of cell cycle, leading to transformation. Recent population based studies also demonstrated that, in uninterrupted combined hormone (estrogen + progestin) replacement therapy (CHRT), progesterone is the contributing factor for the increased risk for mammary...

Cell cycle regulation and pathogenesis of cancer

Cancer has been described as a disease of the cell cycle (North, 1991)- Genomic changes characterised by chromosomal aberrations, translocations and aneuploidy are associated with tumour progression and these arise by cumulative genetic changes resulting from loss of cell cycle control. There have been significant advances in our understanding of the mechanisms of the cell division cycle. Genetic analyses have revealed the involvement in this process of suppressor genes such as the p53 and the retinoblastoma-susceptibility gene, rb. Mutation, allelic loss or inactivation of these genes have been demonstrated in a variety of tumours, leading to the suggestion that the protein products of these genes exert restraint on proliferation of the normal cell. The product of the retinoblastoma-susceptibility gene rb is differentially phosphorylated in relation to the stage of the cell cycle. The rb protein (pi 10 is predominantly underphosphorylated in the Gi phase and becomes...

Association of 16aHydroxylated Estrogens with Breast Cancer Risk

Mation of 16a-hydroxylated estrogen metabolites might be associated with increased risk of developing breast cancer. Their initial studies showed that 2- and 16-hydroxylation of estradiol was minimally affected by age and did not differ between premenopausal and post-menopausal women.129 However, when these enzymatic activities were compared between breast cancer patients (n 33) and matched controls (n 10), 16-hydroxylation was associated with increased risk of breast cancer, whereas the competing 2-hydroxylation pathway was either neutral or associated with decreased risk.135 The investigators suggested that the breast cancer patients had an increased extent of 16a-hydroxylation prior to the onset of the disease, unless the increase was a consequence of the cancer itself. In a subsequent study, using a murine mammary tumor model, Bradlow and associates136 reported a close correlation between the extent of tumor incidence and 16a-hydroxylation, but not 2-hydroxylation, of estra-diol....

The 216aHydroxylated Estrogen Breast Cancer Risk Hypothesis

On the basis of the studies described above, which showed that increased formation of 16a-hydroxylated metabolites relative to 2-hydroxy-lated estrogen metabolites may be associated with an elevated risk of breast cancer, it was hypothesized that a low urinary 2-hydroxyestrone to 16a-hydroxyestrone ratio should be inversely associated with breast cancer risk.144 Development of a competitive-type enzyme immunoas-say (EIA) method for quantifying these metabolites in urine145 allowed the hypothesis to be tested rapidly and relatively inexpensively in a large number of samples. This assay was used in the study by Kabat and associates,144 who measured the metabolites in spot urine from breast cancer cases (n 42) and controls (n 64), including both premenopausal and postmeno-pausal women. Although the 2-hydroxyestrone to 16a-hydroxyestrone ratio was not associated with breast cancer overall, the ratio in the post-menopausal group was significantly lower in the cases (n 23) compared to the...

Risks of Other Cancers in BRCA1BRCA2 Carriers

In addition to the marked excess of breast and ovarian cancer in BRCA1 and BRCA2 carriers, there is also evidence of more moderate risks of other cancer types. The largest study of cancer risks in BRCA1 carriers, based on 699 carrier families, found an overall cancer risk in male carriers very close to that in the general population, but the risk of cancers other than breast or ovarian in female carriers was increased by approximately twofold (44). Specifically, significant excesses were seen for cancers of the corpus uteri, the cervix, the fallopian tubes, and the peritoneum. There was also some evidence of a twofold relative risk of pancreatic cancer in carriers of both sexes and prostate cancer below age 65. In a parallel study based on 173 BRCA2 families, the risk of other cancers was approximately twofold in both male and female carriers (42). The largest excess risk was for prostate cancer, with an estimated 4.7-fold relative risk, increasing to sevenfold in men below age 65. A...

The Effectiveness Of Genetic Toxicity Tests For Identifying Carcinogens And Noncarcinogens

The use of in vitro and in vivo genetic toxicity tests for identifying carcinogens and noncarcinogens are based on several premises (a) tests for both gene mutations and chromosome aberrations are needed (b) mammalian cell tests are more relevant than microbial or other nonmammalian tests, and (c) in vivo mammalian tests are more relevant than in vitro tests. These premises guide most genetic tox-icity testing requirements, whether from government regulatory agencies or industrial chemical or drug development scientists. The premises have recently been re-examined using the databases of chemicals tested by the U.S.-NTP for rodent carcinogenicity and genetic toxicity. The U.S.-NTP databases of carcinogenicity and genetic toxicity test results were used for the evaluation. These studies are characterized by defined, standardized test protocols and evaluation criteria and the availability of the peer-reviewed test data and summary conclusions (47-49). Other, unpublished genetic toxicity...

The Quantitative Burden Based On Cancer Statistics

Understanding the burden of cancer survivorship also requires a quantitative appreciation of the incidence of cancer, the mortality of the disease, and the resulting number of accumulating survivors. The American Cancer Society publishes an annual summary of cancer statistics.14 Based on data from the National Cancer Institute and mortality data from the National Center for Health Statistics, it is estimated that in the United States for 2005, a total of 1,372,910 new cancer cases and 570,280 deaths are expected. Since 1999, cancer has surpassed heart disease as the leading cause of death for persons younger than 85 years. The estimated number of cancer cases in 2005 and the death rate, by various cancer sites, are shown in Figure 1, demonstrating which cancers are most common in incidence and those with the highest mortality.14 The incidence of prostate, lung, and colorectal cancer for men Figure 1. Cancer Cases and Death by Sex in 2005 for the 10 Leading Causes of Cancer. (Adapted...

Other Breast Cancer Genes High Risk Breast Cancer Genes

Breast cancer is involved in two other hereditary syndromes, for which causative genes have been identified. The Li-Fraumeni syndrome is characterized by childhood sarcoma and early-onset breast cancer, brain tumors, and a variety of other cancers. Most families with Li-Fraumeni syndrome appear to be due to germline mutations in the TP53 gene. TP53 mutations confer a very high risk of breast cancer (approaching 100 by age 50) but are much rarer than BRCA1 or BRCA2 mutations (45,46). Cowden's syndrome is a rare syndrome characterized by hamartomas, multiple hamartomas, thyroid cancer, and mucocutaneous lesions and is due to germline mutations in PTEN (61). The risk of breast cancer associated with Cowden's syndrome has not been well estimated, but it is of the order of 30 to 50 lifetime (47).

Low Risk Breast Cancer Genes

A growing list of genes is associated with more moderate risks of breast cancer. The first such gene to be identified was ATM. Mutations in this gene cause the recessive condition Ataxia-Telangiectasia (A-T) (62). Studies dating back over 30 years have suggested that relatives of A-T patients were at increased risk of breast (and perhaps other) cancer (63). This was long regarded as controversial because the studies were small. However, more recent national cohort studies, and direct studies of ATM mutations in breast cancer families and controls, have confirmed that ATM mutations confer an approximately twofold risk of breast cancer (with perhaps a higher relative risk at young ages) (64-67). Another important low-risk susceptibility gene is CHEK2, another DNA repair gene that acts downstream of ATM. Mutations in this gene were first identified in patients with a family history reminiscent of Li-Fraumeni syndrome, and it was therefore suspected that this was another high-risk...

Mechanisms of Cyclin E Deregulation in Cancer

The first report of cyclin E gene amplification as tumor-linked mechanism for elevation of cyclin E expression was based on a breast cancer (BC) derived cell line (15). Subsequently cyclin E gene amplification has been reported at varying frequencies in a variety of different tumor types, particularly gastrointestinal and ovarian cancer (16-18). In BC, however, cyclin E gene amplification is rare (16). We therefore sought to determine if deregulation of cyclin E could be mediated by defects in the cyclin E degradation pathway. First, we analyzed tumor-derived DNA for mutations in cyclin E itself that might impair phosphorylation-dependent ubiquitination. Single stranded conformational polymorphism (SSCP) analysis of DNA from more than 100 tumors yielded no mutations that could account for cyclin E stabilization. Therefore, we turned to analysis of the cyclin E ubiquitation machinery. SCF protein-ubiquitin ligases are characterized by specificity factors, known as F-box proteins that...

Contribution Of Known Genes To Breast Cancer Incidence

The frequency of BRCA1 and BRCA2 mutations in breast cancer cases has been estimated by a number of studies. By pooling data from a number of population-based studies, Thompson and Easton (78) estimated that the prevalences of BRCA1 and BRCA2 mutations among breast cancer patients diagnosed below their mid-30s were approximately 4.6 and 3.5 , respectively. In contrast, the Anglian Breast Cancer Study (the largest population-based study to date) found the prevalences among cases diagnosed between 45 and 54 years of age to be just 0.3 and 1.0 , respectively (79). These studies underestimate the true prevalence of mutations because studies use methods that are not fully sensitive. Indeed, the fraction of mutations that are detected by such studies is somewhat uncertain because some variants in BRCA1 and BRCA2 are of uncertain significance and may or may not be associated with risk. Nevertheless, overall fraction of breast cancer patients in outbred populations carrying BRCA1 and BRCA2...

P53 cancer progression and prognosis

The contribution of abnormal p53 to carcinogenesis has also suggested their potential use in determining cancer prognosis. This gene is located on chromosome 17pl3.1 (Benchimole etal., 1985 Umesh et al, 1988). Loss of heterozygosity on several chromosomes including chromosome 17 frequently occurs in ovarian cancer. Okamoto et al. (1991a) reported allelic loss ofp53 in 16 20 cases. Allelic loss on chromosome 17 is also a common feature of endometrial carcinoma (Okamoto et al., 1991b). Allelic loss at locus THH59 (17q23-ter) shows a more significant association with grade III than with grades I + II ovarian carcinomas. In contrast, association between loss of p53 and tumour grade is poor (Lowry and Atkinson, 1993). Therefore, these authors suggested that there may be a putative suppressor gene on chromosome 17q23-ter whose deletion may be associated with anaplastic ovarian cancers. Over-expression of p53 has been reported to occur in 40-50 of stages III and IV adenocarcinomas of the...

Contribution Of Known Genes To Familial Breast Cancer

An important question is the extent to which the known susceptibility genes can explain the familial aggregation of breast cancer. The simplest assessment of this is the proportion of the familial risk to first-degree relatives of cases that is explicable by each gene. We might term this the familial attributable fraction of each gene. These estimates can then be added over genes, on the assumption that the genes interact either additively or combined on a log scale, if the genes interact multiplicatively. Unlike the population-attributable fraction, the contribution of known genes to the familial risk cannot exceed 100 , so that it provides an assessment of how much genetic variation remains to be explained and is a much more useful concept. Note, however, that this does not reflect the In the case of BRCA1 and BRCA2, the familial attributable fraction can be estimated using data from population-based studies that have performed mutation screening, based on the proportion of cases...

Centrosome Amplification in Cancer

Recent studies implicate centrosome abnormalities in the pathogenesis of cancer (4, 10-14). The term centrosome amplification refers to centrosomes that appear larger than normal, centrosomes that contain more than four centrioles, and or when more than two centrosomes are present within a cell. In addition to these structural abnormalities, amplified centrosomes also show protein hyperphosphorylation and altered functional properties such as an increased microtubule nucleating capacity (4, 8, 15-17). Electron microscope studies revealed supernumerary centrioles in centrosomes of humans and animal model tumors, including leiomyosarcoma, neuroblastoma, glioma, and thymic carcinoid tumors (18-23). Systematic analyses of centrosomes in human breast carcinomas and a mouse model for prostate cancer revealed a range of abnormalities in centrosome structure including excess number of centrioles, increased pericentriolar material, abnormal centriole orientation, and inverted polarity of...

Deregulation of the Centrosome Cycle in Cancer

Centrosome abnormalities in cancer are correlated with loss of p53 function in carcinomas of the breast, head and neck, and prostate, and in neuroectodermal tumors (14, 34, 71). In tumors that retained wild-type p53, amplified centrosomes were frequently associated with overexpression of MDM2, which abrogates p53 function by promoting its degradation (71). Furthermore, gain-of-function p53 mutations and p53 null mice can result in deregulation of centrosome duplication leading to the generation of functionally amplified centrosomes and aberrant mitoses (72-74). Interestingly, in some cancers p53 mutations and cyclin E overexpression may act synergistically since together they increased the frequency of centrosome defects in cultured cells and in mouse models (75). embryonic fibroblasts re-established centrosome homeostasis, overexpression of p21 waf1 only partially restored control of centrosome duplication in p53-null fibroblasts, suggesting that alternative downstream p53 targets...

Computer Applications in Pancreatic Cancer Imaging

There is limited development of automatic approaches for the detection and or diagnosis of pancreatic cancer either from CT or other imaging modalities. This is certainly an area worthy of further investigation and an area identified as in great need of technological advances by the NCI Review Group 2 . Imaging priorities set by the Group have been summarized earlier in this chapter. One of the most interesting recommendation was for a collaborative research and training approach that will link molecular biology, pathology, and imaging as well as for a well documented source of images to support computer applications and image processing 2 .

Hyperplastic and Premalignant Lesions Precursors and Markers of Increased Risk of Breast Cancer

The ductal carcinomas in-situ (DCIS) are well accepted as precursors lesions. They probably have a magnitude of risk in the range of 50 over a ten year period with some variation in both size at time of diagnosis and risk differing between the low and high grade varieties. Presentation of DCIS raises the very important consideration not frequently discussed, the nature of the subsequently developing invasive lesion. The majority ofthe invasive carcinomas developing at least in the short period of several years after initial identification ofan inadequately removed low grade DCIS are low grade invasive cancers, and many ofthese lesions may have prolonged periods without invasion (16, 17). General distribution of cancer risk, in each breast, Cancer in same breast as ALH 70 of the time, and possibly favoring same region in same breast. RR 4.0 x, decreasing with menopause.

Tyrercuzick International Breast Cancer Intervention Study

This is the most recently developed of the breast cancer risk assessment models (32). It was developed using published data regarding BRCA1 and BRCA2 mutation carrier frequencies from a study of mother-daughter pairs (33) and penetrance estimates from the Breast Cancer Linkage Consortium (34) rather than one specific dataset. There are two parts to the model's calculations a genetic part and a personal risk factors part. Like the BRCAPRO model, International Breast Cancer Intervention Study (IBIS) uses Bayesian calculations as a basis for the genetic part of the model. The Bayesian variables used are BRCA1 mutation, BRCA2 mutation, and other genetic risk factor, an as yet unknown low-penetrance gene that is assumed to follow an autosomal-dominant inheritance pattern. Like BOADICEA, IBIS can incorporate exact family relationships and is not restricted to a certain number of first- and second-degree relatives in order to make its assessment. It is also capable of dealing with bilateral...

Iigenetic Changes In Cancer Cells

Based on the somatic cell mutation theory of carcinogenesis proposed in the 1920s (3), gene mutation has long been considered as the primary mechanism of chemical carcinogenesis. The most convincing evidence of this theory comes from studies of inheritable cancers (4, 5) and various tumors that are known to associate with specific genes in humans (2). These findings confirmed the presence of human cancer genes and that they are chromosomally located. Mutations of these genes could result in neoplasm, although allelic mutations alone are not considered sufficient to acquire malignancy (6). Human cancer genes are often tumor suppressor genes, proto-oncogenes, and DNA repair genes. There are about 15 tumor suppressor genes, and more than 100 proto-oncogenes (7). All human and rodent tumor cells contain mutations and chromosome aberrations (8, 9), with multiple, and sometimes specific, DNA sequence changes (10, 11). Studies of neoplastic transformation in cultured cells (12, 13) and in...

Iiigenetic And Epigenetic Mechanisms Of Carcinogenesis

In practice, the genotoxicity of a carcinogen is determined by a battery of genetic toxicology tests. A battery typically consists of three to four mutagenicity tests considered reliable for the detection of mutagens. They are a bacterial mutagen-icity test (such as the Ames test), an in vitro cytogenetic assay in mammalian cells (chromosome aberration), an in vivo cytogenetic assay in rodents (such as micronucleus, chromosome aberration), and sometimes a mammalian cell gene mutation assay (such as mouse lymphoma, Chinese hamster ovary cells) (15). The test procedures and specific requirement of these tests are well established and have been extensively described in two recent international guidelines (16-18). If positive or equivocal findings are observed, additional tests may need to be conducted (such as unscheduled DNA synthesis, DNA adduct), and final decisions are often made by weight of evidence and sound scientific judgment. Based on the results of these tests, a carcinogen is...

Sex Steroid Hormone Receptors and Cancer

Because of their involvement in the regulation of growth control and differentiation during development of the reproductive system, ER, PR, and AR activities are targets of therapeutic intervention in cancers associated with these tissues. Both ER and PR are expressed in breast and uterine cancers, and activation of AR has been implicated in prostatic cancer.306,307 Onco-genes such as c-myc, c-fos, and c-jun are both direct and indirect transcriptional targets for these receptors in these tissues and it is likely that these and other cell cycle regulators are influenced by steroid action.308-310 Clinical use of antagonists and partial agonists of these receptors, such as 4-hydroxytamoxifen and RU486, results in reduction of tumor progression in patients whose tumors are characterized as hormone-responsive. Hormone responsiveness of these tumors often declines following treatment, probably due to second-site mutations that alter the ligand-binding capacity of the receptor.7...

Vsv As A Therapy Against Cancer

Our data, as well as that of others, also indicated that whereas normal cells treated with IFN were protected from VSV infection, transformed cells were much less protected (21,34). Even many types of IFN-treated tumor cells eventually succumbed to virus infection, speculatively inferring a common defect in innate immune responses (61,62). Given our above data, we naturally examined the status of PKR in VSV-susceptible tumor cells. For example, it was plausible that PKR could be defective in cells sensitive to VSV. However, our data indicated that PKR was functional in many cases and remained able to phosphorylate eIF2a (23). We subsequently noted that a key translation factor that recognized phosphorylated eIF2a and slowed protein synthesis, referred to as eIF2B, was frequently defective (23). The consequences of this were that phosphorylated eIF2a did not impede translation rates. This may assist viral translation and allow VSV to replicate faster than an antiviral state involving...

Aromatase Transgenic Mice are Susceptible to Carcinogens

To test the hypothesis that tissue E-induced preneoplastic changes induced may be susceptible to carcinogens like DMBA, and that exposure to these carcinogens may result in acceleration and or increase in the incidence of BC (21). Exposure to a single sub-threshold concentrations of DMBA (0.5 (ig mouse) resulted in development of MG tumors in 25-1 of the transgenic animals and non in wild type mice. All the DMBA-exposed transgenic females had microscopic evidence of tumor formation neoplastic progression. When the ARO transgenic female animals were exposed to a higher DMBA dose (1.0 Hg mouse week 4 weeks), more than 50 developed palpable MG tumors within 4.0 mo, while 100 show microscopic evidence of tumor formation Previous data (6, 13, 22) suggest that the ERa has a negative regulatory effect on EGFR expression and its ligands. These results are consistent with the clinical observations that loss of ERa in BC results in the upregulation of growth factors like TGFa, leading to a more...

Human Versus Rodent Carcinogenesis

Of the more than 400 rodent chemical carcinogens in the IARC carcinogen list (group 2), only about 50 human chemical carcinogens (group 1) have been identified so far (101). This large difference may be explained by the lack of sufficient epidemiological studies of rodent carcinogens, which are required for their evaluation as human carcinogens. However, it is also possible that there are inherent genetic and biochemical differences between humans' and rodents' response to chemical carcinogenesis. Evidence to support this proposition is discussed below. A very significant finding, but seldom discussed, is the unique resistance of human cells to chemical carcinogenesis in culture, as demonstrated in in vitro neoplastic transformation studies. Neoplastic transformation in vitro means the immortalization of a primary cell culture to become established cell lines and to acquire neoplastic phenotypes, including the ability to form a tumor in immuno-deficient mice. In these studies, rodent...

Genetically Engineered VSV as a Gene Therapy Tool Against Cancer

Oncolytic studies indicated that wild type VSV exhibited considerable potential as an anticancer agent. However, the ability to modify VSV through genetic engineering obviously affords the prospect of creating new generations of custom-made VSV vectors that contain immunomodulatory and or suicide cassettes designed to increase their antitumor activity. In order to begin evaluating whether genetically engineered VSV carrying tumor-killing cassettes could be created and whether such viruses were more efficacious in tumor therapy than the wild-type VSV, we developed VSV vectors carrying, as models, the herpesvirus TK suicide cassette or the cytokine gene interleukin-4 (IL-4). The foreign genes were cloned as additional transcription units between the VSV G and L genes and all viruses were grown to exceptionally high titers (71,103). TK protein was synthesized to extremely high levels and was functional, being able to phosphorylate ganciclovirs (GCV). Recombinant viruses also retained...

Retinoblastoma susceptibility gene rb abnormalities in cancer

Retinoblastoma is a paediatric cancer arising in the retina of the eye. This disease occurs in both hereditary and sporadic forms. There are, however, marked differences in their patterns of development and incidence. In the hereditary form the disease is bilateral and multifocal but sporadic retinoblastoma is unilateral and unifocal. The incidence of the familial tumour is higher than the sporadic form. These features of retinoblastoma and statistical analyses of incidence led to the 'two-hit' hypothesis proposed by Knudson (1971). The suggestion was that one mutated rb allele was inherited and occurred in all cells, including germ cells, of the progeny and that a mutation of the second allele would lead to the development of the tumour. It was reported many years ago that retinoblastoma was induced by a bi-allelic inactivation and the retinoblastoma- The rb gene is expressed in all normal tissues and cell lines (Lee et al., 1987b). It is expressed in a mutated form or absent in...

Peroxisome Proliferatoractivated Receptors And Cancer

The ability of PPARy to promote and establish differentiated phenotypes in at least two cell types (i.e., adipose and macrophage) suggests that PPARy activators may also be useful to block proliferation in malignant cells that express this receptor. In fact, preliminary studies demonstrate that in breast cancer and liposar-coma cell lines PPARy and or RXR ligands are capable of limiting cell growth by promoting dif-ferentiation.407,408 This differentiation therapy is similar in concept to RA treatment in APL, where activation of the NR interferes with or su-percedes proliferative growth signals by unknown mechanisms. The ability of PPARy to promote differentiation, however, is likely tissue- and context-dependent. For example, activation of PPARy in the colon of the adenoma-tous polyposis coli (APC)-deficient Min mouse (a model of familial adenomatous polyposis) results in an increase in colon polyp number.397,409 However, studies in colon cancer cell lines found that...

Molecular Genetics Of Cancer

The transformation of a normal to a malignant cell is a multistage process during which the orderly processes of proliferation and differentiation become uncoupled and the balance between proliferation and cell death is disturbed. Cancer cells proliferate unceasingly and do not proceed along normal maturation pathways. Cells cultured in the laboratory undergo two changes in phenotype (physical characteristics) during the route to malignancy Fully transformed cells are biologically 'malignant' but not necessarily 'tumourigenic' or 'metastatic' in an experimental animal. To be so, additional changes of phenotype are required. Clinically, a 'benign' neoplasm, although continually growing, is limited to its primary site. A 'malignant' neoplasm may either form an in situ cancer, showing only unrestrained growth, or invade and metastasize. Only an invasive cancer is truly malignant to its host. Cancer is now regarded as a multi-factoral disease of the cell genome which undergoes a series of...

Surgery for Testicular Cancer Radical Orchiectomy

Testicular cancer remains the most curable solid tumor in men. Careful histologic diagnosis and prompt evaluation for metastatic disease are essential for the selection of appropriate treatment. The first surgical step in the management of testicular cancer is inguinal orchiectomy. In the past, before the advent of good techniques for testicular imaging, inguinal exploration with open biopsy of the testis was the primary method of making a definitive diagnosis of testicular cancer. Now, scrotal ultrasonography is nearly 100 accurate in identifying a tumor in the testis, and it is rarely necessary to perform a truly exploratory surgery.1,2

History Of Parvovirus And Cancer

Since the discovery of parvoviruses, there has been significant advance on the relationship between parvoviruses and cancer. Epidemiological surveys in humans have revealed a correlation between serological evidence of parvoviral infection and lower incidence of certain human cancers (7,8). In vivo studies have demonstrated that animals infected with parvoviruses exhibited increased protection against chemical carcinogen- and virus-induced tumorigenesis (9). Several in vitro studies have also reported inhibition of cellular transformation by parvoviruses and interestingly, preferential killing of established tumor cell lines by parvovirus infection compared with normal cells (9). Results of these studies have led to the belief of possible interference with the induction of malignant transformation as well as survival and proliferation of tumor cells. Subsequent studies have provided molecular evidence on the role of NS proteins of parvoviruses in oncosuppression (10-12). More...

Presentation Of Testicular Cancer

The clinical presentation of testicular cancer is usually quite obvious. The typical patient is a man aged 17 to 45 years who notices a growing and relatively painless mass in the scrotum and seeks medical attention. However, as many as 10 of patients present with atypical complaints, such as sudden pain in the scrotum, a new-onset hydrocele, or recent trauma. Some patients are misdiagnosed as having epididymitis, causing an unnecessary delay in diagnosis. A high index of suspicion is required when evaluating any man in this age group with testicular complaints, and the possibility of testicular cancer must be in the differential diagnosis. Patients diagnosed with presumed epididymitis should be observed until the testicular examination result returns to normal, which might take several months. Any patient with nonspecific orchialgia who is completely normal on examination should probably have at least one follow-up examination in 3 to 6 months to ensure that a small tumor was not...

Preimplantation And Prenatal Testing For Hereditary Breast Cancer

Another emerging issue concerns the use of preimplantation genetic diagnosis (PGD) (89) and prenatal diagnosis for hereditary cancer syndromes. A recent review of this issue cited 55 reports of testing for these purposes (90). Both technologies have been utilized in families with Li-Fraumeni syndrome, and PGD has been used by parents at risk for having a child with a BRCA1 2 mutation (90). The ethical issues raised by these procedures share some similarities but also have some unique features. The option of prenatal diagnosis raises the question of appropriate use of this technology. In most developed countries, the offer of prenatal diagnosis and selective termination is generally considered acceptable when the condition is a childhood onset disorder with significant morbidity and premature mortality. In contrast, the application of prenatal diagnosis to a disorder such as hereditary breast ovarian cancer syndrome is controversial. In the case of PGD, the strongest argument in favor...

Hormonal Prevention of Breast Cancer Mimicking the Protective Effect of Pregnancy

Hormonal prevention strategies have used exogenous hormonal treatment to mimic the protective effect of pregnancy against BC. Huggins, et al. (29) reported that high levels of E2 and P given for 30 days beginning 15 days after DMBA administration inhibited MC in SD rats. They proposed that treatment with high levels of these hormones destroyed the potential cancer cells. Grubbs, et al. (30, 31) and McCormick and Moon (32) demonstrated that treatment of SD rats with high levels of and P, or alone following treatment with MNU, a direct acting chemical carcinogen, was as effective as ovariectomy in preventing MC. Grubbs (31) suggested that the primary action ofthe hormones was to cause differentiation of the pre-neoplastic cells. Recent studies have reported on persistently altered expression of genes in the mammary glands ofparous rats (33). They reported that certain genes involved in growth promotion are persistently down regulated in mammary glands. They also reported that TGF-P3 and...

Causative Factors for Refractoriness of Parous Rats to Mammary Carcinogenesis

Parous Rats Treated with MNU Have a High Incidence of Latent Mammary Cancers. In collaboration with Dr. Airo Tsubura, the role ofparity before and after MNU treatment was studied (24). Pregnancy and lactation before (22 ) or after (25 ) MNU treatment reduced the incidence of frank MCs compared to age- matched nulliparous females (72 ) and (94 ), respectively. At termination, rats that underwent pregnancy prior to MNU (67 ) or after MNU (50 ) both had high incidences of microscopic latent mammary cancers. These findings suggest that MCs are initiated at a fairly high incidence in parous rats, but many ofthese cancers do not progress to frank MCs during the 12 mo after MNU treatment. Thus, these studies indicate that the MEC are highly susceptible to initiation of carcinogenesis and are not completely refractory to the carcinogenic process. Refractoriness to Frank Mammary Carcinogenesis in Parous Rats can be Overcome by Hormone Treatment. In a separate study, MNU was given to parous...

Recombinant Apv For Cancer Gene Therapy

Despite certain limitations in the production of recombinant APV, recent reports indicated successful production and transduction in vivo leading to therapeutic efficacy against tumors in preclinical animal models. Recombinant H1 encoding either IL-2 or monocyte chemotactic protein (MCP-1) replacing the capsid gene was found to reduce the growth of transduced HeLa cells as xenograft in nude mice (53). Recombinant MVM encoding an antiangiogenic chemokine IP-10 significantly retarded the growth of syngeneic tumors in immunocompetent mouse model of Kaposi's sarcoma (54). The concept of utilizing replicating APV in cancer gene therapy has been recently published using a colon cancer cell line constitutively overexpressing a gene of the wnt signaling pathway (55). In these studies, the expression from P4 promoter of MVM was modified to include binding sites for the heterodimeric P-catenin Tcf transcription factor. The mutant virus not only rendered susceptibility for lysis of...

The Promotional Environment for Mammary Carcinogenesis is Decreased in the Parous Rats Compared to that of Nulliparous

Nulliparous Rats Mammogenic Hormones and Mammary Epithelial Cells. Administration of MNU to 50-60-day old nulliparous rats, 120-day-old nulliparous rats, and 120-day-old parous rats, resulted in a high incidence of mammary cancers in the nulliparous rats (97 in 50-60 day old rats 75 in 120 day old rats), no MCs developed in the parous rats (26). The concentrations in the serum of mammotropic hormones were measured at the time of MNU treatment. GH concentration was reduced in parous rats (16.1 ng ml) compared to young nulliparous (59.3 ng ml), and age matched nulliparous (38.6 ng ml). PRL levels were 14.6 ng ml in parous, 25.7 ng ml in young nulliparous, and 25.5 ng ml in age-matched nulliparous. Levels of E2, P, corticosterone, and thyroxine were not different in the three groups. The concentrations of ERa and EGFR were decreased in the mammary glands of parous rats (3.5 fmol mg protein, 3,500 cpm mg) compared to young nulliparous (12.1 fmol mg, 5000 cpm mg), and...

Adenoassociated Virus For Cancer Gene Therapy

Similar to the APV, wild-type AAV has also been identified to possess antioncogenic properties (62,63). Although rAAV vectors are relatively less studied in cancer gene therapy, those reported so far indicate their future potential. In addition, whereas most of the cancer gene therapy strategies target tumor cells directly for increasing therapeutic benefit, targeting normal cells that regulate key events conducive for tumor growth is becoming a promising alternative for cancer therapy. For direct targeting of tumor cells, although long-term expression is not required, this may be beneficial in strategies aimed at targeting normal cells, such as tumor endothelium, that exert a sustained control over tumor growth. In this regard, AAV remains a promising vector for cancer gene therapy. The last few years have also seen increased application of AAV serotypes other than the widely used serotype 2-based vectors (64-68). Variations in the amino acid sequences of capsid protein between...

Identifying Epidemiologic and Genetic Risk Factors for Colorectal Cancer

Absolute risk is the most easily interpreted risk measure and is often specified in terms of risk per time unit per individual. Using the definitions in Table 6-1, the absolute risk among exposed individuals (e.g., individuals exposed to an environmental carcinogen or with a disease-causing genotype) per unit time is a (a + c). The relative risk is the risk for disease among individuals who have been exposed to a risk factor divided by the risk for disease among individuals who have not been exposed to that risk factor a (a + c) b (b + d) . Finally, the odds ratio is the ratio of the exposed individuals among the diseased to the exposed individuals among the nondiseased, divided by the ratio of the nonexposed individuals among the diseased to the nonexposed individuals among the

Development of Short Term Hormone Treatments for Prevention of MNUinduced Mammary Carcinogenesis in Rats

Inhibitor) for 3 weeks beginning at 9 weeks of age (10). Both of these treatments caused late pregnancy-like lobule development in mammary glands. 90 of the control rats, 73 ofthe PPZ-treated, and only 9 ofthe rats treated with sustained exposure to E2 + P in silastic capsules developed mammary cancer during the 9 mo-period of observation following MNU treatment. The E2 + P-treated rats developed 93 fewer MCs compared to controls not receiving hormonal treatment. Both PPZ and treatments induced, similar to pregnancy, lobular growth, secretory differentiation, and involution after cessation oftreatment ofthe mammary gland. Assays of blood levels of E2 and P indicate that after PPZ treatment, only the P levels (P 101.5 ng ml, E2 16.6 pg ml,) were increased to pregnancy levels. There was no increase in circulating E2 levels compared to untreated control virgin rats (E2 18.3 pg ml, P 12.7 ng ml). Treatmentwith E2 + P resulted in pregnancy levels of E2 (168.8 pg ml), and lower than...

Adenoassociated Virusmediated Longterm Expression For Cancer Therapy

A recent study on the potential use of rAAV encoding sFlt1 in ovarian cancer reported that transduction of a human ovarian cancer cell line RMG-1 with AAV-sFlt1 in vitro followed by intraperitoneal administration in nude mice resulted in a decrease in proliferative and metastatic indices suggesting the feasibility of localized AAV-sFlt1 antiangiogenic gene therapy (101). However, a major limitation of intratumoral delivery of rAAV is the inefficient rate of transduction and limited dispersion of the vector in tumor cells. Also, unlike genetic metabolic diseases, which require only partial amounts of the deficient protein enzyme for phenotypic correction of the disease, tumor therapy requires inhibition of the tumor growth in toto. Antiangiogenic therapy, in particular, requires a constant level of the inhibitory factor(s) for sustained therapeutic effect. Recent studies with rAAV encoding antiangiogenic factors angiostatin and endostatin have also shown in vivo antitumor efficacy...

Recombinant Aavmediated Cancer Gene Therapy As Adjuvant Therapy

Based on several studies over the last decade, it is becoming increasingly clear that gene therapy includes a repertoire of cancer treatment paradigms. At the same time, limitations in both target definition and vector efficacy need to be overcome to utilize this as an exclusive therapeutic modality. However, important to this discussion is the realization that gene therapy can be combined with other traditional treatments as an adjuvant therapy. For many of the solid tumors, surgery, chemotherapy, radiation therapy, and hormonal therapy constitute the major therapeutic measures. Despite advances in early detection and successful initial control, many tumors recur yielding a much more ominous prognosis. In these situations, it may be more appropriate to advance our ability to effectively utilize gene therapy to prevent such recurrences. These adjunct therapies may well be targeted toward secondary cellular events such as antiangiogenesis or toward elicitation of host immunity for a...

Basic Principles And Concepts Of Mechanismbased Sar In Predicting Carcinogenicity Of Chemicals

Basically, mechanism-based SAR analysis involves comparison of the chemical in question with structurally related compounds with known carcinogenic activity, identification of structural moiety(ies) or fragment(s) that may contribute to carcinogenic activity through a perceived or postulated mechanism, and evaluating the modifying role of the rest of the molecule to which the structural moiety fragment is attached. Since the pioneer work of the Millers (2), which conceptualized electrophiles as the ultimate carcinogen to interact with DNA to initiate carcinogenesis, considerable knowledge of the mechanisms of chemical carcino-genesis has accrued. For many carcinogen classes, the molecular basis of carcinogenic activity is now known in considerable detail, and the concept of electrophiles provides the most probable rationale for their carcinogenic action. The knowledge of molecular mechanisms and other factors that affect carcinogenesis by various types of chemical carcinogens has...

Hypermethylation and Colorectal Cancer

Tumor suppressor genes, such as p16 and HMLH1, are inactivated in colorectal cancers by mutation, deletion, or methylation (Kane et al, 1997). Abnormal patterns of DNA methylation are common molecular changes in human neoplasms, including colorectal cancer. p16 methylation is closely associated with K-ras mutations (Guan et al, 1999). Also, aberrant methylation is associated with the microsatellite instability (MSI) pheno-type in colorectal cancer. Recent studies showed that hypermethylation of the MLH1 promoter region is common in MSI-positive sporadic colorec-tal cancers (Cunningham et al, 1998). Hypermethylation of MLH1 is also associated with the absence of immunoreactive MLH1 protein (Miyakura et al, 2001). Most sporadic cancers with an MSI phenotype are hypermethylated in the promoter region of hMLHl, whereas mutations and allelic loss cause the MSI phenotype in most HNPCC cancers (Wheeler et al, 2000).

Environmental Factors Related to Hereditary and Familial Colorectal Cancer

Familial colorectal cancer may reflect the influence of multiple genetic factors along with environmental cofactors. Fuchs et al (2002) found that women with high folate intake who had a first-degree relative with colo-rectal cancer were not at increased risk for colorectal cancer. However, women with low folate intake who had a relative with colorectal cancer had about a 2.5-fold increased relative risk for colorectal cancer compared with women with low folate intake and no family history of colorectal cancer. The effect of environmental exposures on risk for cancer among individuals with inherited susceptibility has not yet been studied. However, exposures, such as low folate intake, that are thought to impair DNA repair capacity would be expected to further increase the risk for colorectal cancer among individuals with mismatch repair defects. Several studies have elucidated relationships between certain environmental exposures and genetic markers in colorectal carcinogenesis. For...

Principles Of Cancer Treatment Curability

The logical objective of the treatment of cancer is destruction of all cancer cells. The disease is then eradicated and the patient 'clinically cured'. This definition of clinical cure is impractical as it can only be proven by a complete search for asymptomatic deposits of tumour on death. However, clinical cure should follow the complete removal of all non-invasive cancers, and also a number of small invasive cancers, particularly in superficial sites, which have not metastasized. Life is personal and freedom from recurrence of the cancer during the remainder of a patient's lifetime constitutes 'personal cure'. This does not rule out the possibility that the disease is present in asymptomatic form and is clearly dependent upon the duration of life following its diagnosis. By this definition, the patient who is killed in a road accident on the way home from hospital following the palliative resection of an incurable gastric cancer is 'cured' A third definition of cure is 'statistical...

Aromatase Inhibitors and Treatment of Breast Cancer

Neoadjuvant protocols in which therapy is given with the primary cancer remaining within the breast allow tumor responses to be assessed in individual patients by monitoring changes in tumor volume during treatment. Impressive anti-tumor effects have been observed in selected groups of patients with estrogen receptor (ER)-a rich cancers. (19, 35) (Table 2). Marked reduction in tumor size provides clinical benefits, and many patients who initially required mastectomy or were inoperable can be treated by more conservative breast surgery (19, 35) (Table 3).

Is the wafl dpi gene altered in cancer

The wafl cipl gene functions as a downstream target for the p53 gene in its function of GrS transition control. As we have seen before, wafl cip can function independently of p53 to produce Gi arrest and therefore can be regarded as a suppressor gene itself. Using this reasoning some attempts have been made to seek possible aberrations in wafl cipl in human cancers. Marchetti et al. (1995c) investigated a large number of breast carcinomas, non-small cell lung tumours and ovarian adenocarcinomas for mutations in the gene. A polymorphism at codon 31 was seen in a small proportion (16 out of 183) of cancers and no mutations were encountered in the wafl cipl open reading frame. Polymorphism of codon 31 has also been reported in colorectal cancer and somatic mutations have not been found in codons 9 through 139 that were screened (Li YJ et al, 1995). Multiple polymorphisms were seen in human brain tumours, most frequently of codon 31 - again there were no somatic mutations (Koopmann et al,...

Familial Clustering Of Hormoneresponsive Cancers

Our primary topic of discussion is the role of inherited variation in gene sequence and its impact on cancer risk in the general population. We begin by examining the evidence that genetics (inherited variation in genome sequence) actually plays a role in the risk of cancer. The strongest data involve familial aggregation, showing that rates of disease are higher in the families of cancer patients than in the population at large. Of course, families are characterized by shared environment as well as shared genes. These factors are typically disentangled by comparing rates of concordance in monozy-gotic (MZ) and dizygotic (DZ) twin pairs.7 Monozygotic twins are 100 identical in genome sequence, whereas DZ twins are identical (on average) across only 50 of their DNA the method relies on the assumption that both types of twins share environmental influences to a similar degree. To the greatest degree possible, comparison of MZ to DZ twins separates the effects of genes and the...

Estrogens Aromatase and Risk of Breast Cancer

These observations provide the rationale for the use of endocrine therapy as preventative measures against BC in women with high risk ofthe disease. Four trials using tamoxifen have been published (55-57), as has a fifth trial using raloxifene (58). Although there are differences among studies, a recent metaanalysis of the tamoxifen trials indicated that results were compatible with a 42 reduction in short term incidence of breast cancer with tamoxifen use (59).

Role of Estrogens in the Development of Breast Cancer

The mechanism by which Es increase risk of overt BC is still the subject of debate (Figure 4). Es can stimulate the proliferation of breast epithelial cells, leading to genetic mistakes and a transformed cellular phenotype (72). Additionally, Es can accelerate the growth of occult cancers resulting in increased incidence of overt disease (73). These promotional properties of Es appear to be largely mediated through ER signaling system. Consequently, both SERMs and aromatase inhibitors should attenuate such promotion. Figure 4. Mechanisms whereby E may cause breast cancer (1) via the ER, (2) via metabolism of E. Note that anti-estrogens block only ER-mediated events, whereas aromatase inhibitors block both ER and metabolic pathways However, evidence is accumulating that E metabolites are genotoxic (74). In particular, metabolism of Es via catechols (2- 4-hydroxyestradiol or hydroxyestrone) may produce reactive quinones which can directly interact with and mutate DNA, initiating...

Intrachromosomal recombination in tumour suppressor genes in cancer

Genomic deletions occur in tumour suppressor genes and genes regulating cell proliferation and such mutations are encountered frequently in the pathogenesis and progression of cancer. As discussed elsewhere in this book (see Chapter 3), homologous and non-homologous intrachromosomal recombination or unequal exchanges and recombination between chromatids can bring about the duplication of genetic material, which is often visualised as HSRs or DMs. Drug resistant cell lines contain DMs and HSRs, which represent amplification of the multi-drug resistance gene. These DMs not only contain amplified DNA but they also harbour Alu repeats (Sognier et al., 1994), and one could tacitly assume that Alu might have played some part in the amplification process. The BRCA1 gene is associated with susceptibility to develop breast and ovarian cancer. It may be described as a classical suppressor gene, shows LOH in cancer families and somatic mutations may also occur in breast and ovarian cancers. The...

Aromatase Inhibitors and Prevention of Breast Cancer

Effects ofthird generation inhibitors make long-term monitoring of bone and lipid profiles mandatory. Ongoing adjuvant trials with aromatase inhibitors provide information on the incidence ofnew contralateral BCs and side-effect profiles. The large ATAC trial shows a significant reduction in contralateral cancer in the aromatase inhibitor (anastrozole) group compared with tamoxifen (35 vs 20, p

Strategies Using Nonviral Vectors In Cancer Gene Therapy

Various nonviral vector systems have been used to deliver DNA into cancer cells to induce an antitumor effect. Naked DNA encoding genes ranging from cytokine genes to tumor antigen genes have been delivered alone (63), by gene gun (64,65), or by electroporation (66,67), resulting in significantly induced cytokine levels or specific antigen expression. Electroporation has also been used to introduce plasmids that encode antisense RNA against E6 and E7 mRNA to human papilloma virus (HPV) expressing cancer cells, which resulted in a significant inhibition of tumor growth (68). Another approach involved gene gun-mediated delivery of heat-shock protein 70 (Hsp70) linked to the HPV16 E7 tumor antigen gene into antigen presenting cells (APCs). It led to an enhanced E7-specific immune response of lymphocytes after exposure to these transfected APCs (69). LPD also plays an increasingly important role in antitumor gene therapy. An interesting method is to deliver a plasmid containing an...

Further Chemotherapy For Radically Resected Residual Cancer

The presence of viable cancer cells in completely resected residual masses carries the worst prognosis when compared with the presence of mature teratoma or necrosis alone (see also Chapter 16).26,33 Since the study by Einhorn and colleagues,37 which reported a dismal outcome for all 18 patients with residual cancer at postchemotherapy surgery who received no further therapy, many investigators have opted for the routine use of postoperative adjuvant chemotherapy.2,5,9,11,12,24,26,33 No compelling evidence has existed to confirm whether adjuvant chemotherapy for consolidation is justified in this setting. Thus, my colleagues and I recently challenged this approach as we found no difference in the 5-year survival in a retrospective study of 49 evaluable patients who were treated (24 patients) or not treated (25 patients) with adjuvant chemotherapy following complete resection of residual cancer after first-line (30 patients) or salvage (19 patients) chemotherapy.38,39 An international...

Breast Cancer Risk In Males

Familial clustering of female breast cancer was demonstrated as early as 1926 (81), and epidemiological studies have shown that although both men and women with breast cancer are more likely to have family histories in first-degree relatives than unaffected individuals, men with breast cancer were even more likely to have a first-degree relative with ovarian cancer than affected women (82,83). It is noteworthy that initial linkage studies of BRCA1 did not reveal an association with male breast cancer (14,84). Linkage studies for BRCA2, on the other hand, did contain male breast cancer cases (16). Germline analyses of 50 men affected with breast cancer unselected for family history revealed that 14 of these men carried a BRCA2 mutation (85). Easton et al. (52), in a study of two large kindreds linked to BRCA2, estimated the cumulative risk of breast cancer in male carriers to be 6.3 by the age of 70 years. In an analysis of 164 BRCA2 kindreds, a similar estimate for cumulative risk...

Roles Of Sar In Cancer Risk Assessment

In the absence of adequate epidemiologic data and based on the findings that virtually all known human carcinogens are also rodent carcinogens, data from lifetime exposure animal bioassays are primarily used for identifying chemical substances that may be associated with carcinogenic effects in humans. However, the high cost of testing, the large number of animals used in 2-year rodent bioassays, and the huge number of chemicals for which carcinogenicity data do not exist have made it impractical and inhibitory to test each of the thousands of existing chemicals for carcinogenicity. Meanwhile, government health regulatory agencies are under increasing mandate to screen large lists of existing chemicals in commerce and the environment for carcinogenic and other toxicologic effects. Structure-activity relationship is serving an increasingly important role in the risk assessment process as the first line approach in hazard identification, prioritizing chemicals for testing, designing...

Molecular Mechanisms ofOncogenes in Carcinogenesis 241 Platelet Derived Growth Factor and Its Receptors

EGF receptors are commonly overexpressed in a number of epithelial malignancies and are often associated with an aggressive phenotype. They are overexpressed in over 50 of non-small-cell lung cancers (NSCLC), head and neck squamous cell carcinoma (HNSCC), and colon cancers, along with overexpression of one or more other EGFR family members (21,23,24). Karyotypic abnormalities, including the translocation, duplication deletion, and loss of chromosomes, have long been recognized. Most chromosomal abnormalities do not correlate with cancer types, suggesting that these abnormalities are likely secondary events and reflecting the inherent genetic instability of cancer cells. In contrast, some types of malignancies consistently undergo certain chromosomal changes. For example, a reciprocal translocation between chromosomes 9 and 22 occurs in the leukemia cells of more than 90 of patients with chronic myelogenous leukemia (CML) (28). As a result of this translocation, the abl proto-oncogene,...

Cancers Other Than Breast and Ovarian Cancer

Table 1 groups studies, by type, that have examined the association of cancers other than breast and ovarian FT cancers with BRCA1 2 mutations, or in families with breast and or ovarian cancer. Inclusion in the table was restricted to claims of statistically significant findings. Colorectal Cancer Early linkage studies and family-based studies in which there was no genotyping of colorectal cancer cases observed significant associations between BRCA1 2 mutations Table 1 Genotype Phenotype Correlation Studies, Listed by Type (see text), Associating BRCA1 2 Mutations with Cancer Risks potential No. of Colon Kidney bile Fallopian Squamous cancers The Breast Cancer Linkage Consortium, 1999 Abbreviations'. AJ, Ashkenazi Jews BC, breast cancer CR, carriers' relatives FT, fallopian tube n, noncarriers' relatives NS, not significant PPC, primary peritoneal carcinoma R, rectal only X, not reported. and colorectal cancers. Using linkage kindreds, Ford et al. (51) estimated the RR for colon...

Investigational Measures for Colorectal Cancer Screening

Two new methodologies, virtual colonoscopy (also known as computed tomography colonography) and stool-based testing for mutated DNA, are exciting and of considerable interest. Virtual colonoscopy entails the use of spiral computed tomography with very thin cuts (otherwise, small lesions would be missed) and new computer techniques for 3-dimensional reconstruction. Currently, standard bowel preparations are required and elimination of all effluent is important. Efforts are under way to develop oral contrast agents that mix with enteral contents so that they may be subtracted from images, eliminating the bowel preparation, which many patients find more noxious than the colonoscopy itself. Several singleinstitution trials have yielded virtual colonoscopy sensitivities of greater than 90 for the detection of adenomas larger than 1 cm. In one study (Pickhardt et al, 2003) of CT with 3-dimensional endoluminal display vs conventional colonoscopy in 1233 asymptomatic adults, CT colonography...

Project Title Dietary Etilogies Of Heart Disease And Cancer

Summary (Adapted from Investigator's Abstract) The authors propose to continue the follow-up of 51,529 male health professionals, aged 40 to 75 years in 1986, to address a series of dietary hypotheses related to risk of coronary heart disease, stroke, and peripheral vascular disease. Diet has been assessed in 1986, 1990, and 1994 by a semiquantitative food frequency questionnaire developed and refined by the group over the last 15 years. Detailed studies in a subsample of participants demonstrate that this questionnaire performs well the average correlation between the questionnaire and 14 days of diet recording for 16 nutrients of interest was 0.66. This study population has substantial variation in dietary intake, for example, fat intake varies from 25 to 42 of calories between extreme quintiles. Body fat distribution (assessed by waist and hip circumferences) has been measured twice (1987 and 1996) and weight is updated during every 2-year cycle. The first three follow-up cycles...

Interaction of Oncogenes and Tumor Suppressor Genes in Human Carcinogenesis

Humans are the highest class of organism on earth, likewise, human carcinogenesis is more complicated than carcinogenesis in any other organisms. For example, a single activated oncogene can cause neoplastic transformation in avians and rodents. In humans, however, expression of a single oncogene such as myc or ras in normal human cells induces only apoptosis or senescence (31). This has led to the widely accepted concept of multistep carcinogenesis involving the activation of multiple cellular onco-genes and the inactivation of tumor suppressor genes. Often, several tumor suppressor genes form pathways with other tumor suppressor genes or with oncogenes that govern cell growth, apoptosis, differentiation, and genome integrity (31). A good example is the Rb pathway. In its nonphosphorylated form, Rb inhibits the cell cycle by blocking DNA synthesis (S-phase). It does so by binding to proteins of the E2F family of transcriptional factors and inhibiting their functions as...

Colon Cancer Chemoprevention

Chemoprevention of colorectal cancer has come to imply the use of orally administered agents, whether dietary or strictly pharmacologic, to reduce the risk of developing adenocarcinoma. Epidemiologic data strongly point to geographic differences in colo-rectal cancer incidence. Rates have been highest in northwestern Europe, North America, Oceania, and Argentina and lowest in sub-Sahara Africa. As such differences were explored in greater detail, specific factors in the diet came to be implicated. Several studies have led to the conclusion that diets high in animal fat and total energy intake increased risk, while diets high in total fiber, whether fruit, vegetable, or bran, were associated with lower risk. Although well accepted as a key paradigm in carcinogenesis and taken for granted in many ways, the adenoma-to-carcinoma sequence is very important to our understanding of chemoprevention. Even though most adenomas do not progress to invasive adenocarcinoma, essentially all...

Oncogenes Tumor Suppressor Genes And Apoptosisinducing Genes In Cancer Gene Therapy

Recent advances in molecular biology and biotechnology have led to the development of nucleic acid-based medicines that directly target the genetic alterations or molecular mechanisms required for tumorigenesis or for maintenance of the malignant phenotype. The rationale is that local intratumoral expression of the desired therapeutic proteins may exert a constant therapeutic effect at the cancer site without causing substantial systemic toxicity. A growing body of evidence indicates that enforced overexpression or downregulation of various genetically encoded functions can directly or indirectly exert a therapeutic benefit by augmenting the response to conventional therapeutics (37).

Establishment of Models for Studying Prostate Cancer Cell Progression

We believe that a better understanding of the process of PCA cell progression is very important for establishing better methods for PCA treatment. To investigate PCA progression, we established a model system (Figure 2) using a clone derived from the human PCA cell line, LNCaP, whose growth was dependent on the presence of nanomolar concentrations of testosterone, 5a-DHT or 17 P-hydroxy-17-methyl-estra-4,9,11 -trien-3 -one (R1881) (21-23). The original cancer cell (named LNCaP 104-S) population was cultured through weekly passages and after about 40-70 passages in A-depleted culture medium, these cells progressed to A-independent cancer cells that we named LNCaP 104-R1 cells. These cells can grow well in culture without A. After continuous culture of 104-R1 cells in A-depleted medium for 60-120 additional passages, these 104-R1 cells were transformed into faster-growing cells, named 104-R2 cells. This transition of A-dependent 104-S cells to A-independent 104-R1 and 104-R2 cells is...

Propionibacteria and cancer

Among the beneficial effects that have been attributed to probiotics, the prevention of cancer, with a main focus on colon cancer, constitutes the most promising and probably the most controversial potential. As stated by J. Rafter, there is no direct evidence for cancer suppression in humans as a result of probiotic consumption (Rafter, 2003). However, there is wealth of indirect evidence, based on experimental work, both in vivo and in vitro, of anticancer properties of some probiotics. Probiotics may interfere with the development of cancer via binding and degradation of carcinogens, production of anti-mutagenic compounds, modulation of the intestinal microbiota and or metabolic activities or by enhancing the host's immune response. Several dairy propionibacteria species were shown to induce apoptosis of two human colorectal cancer cell lines in vitro (Jan et al., 2002a). This effect was attributed to the secretion by propionibacteria of short chain fatty acids, acetate and...

Hereditary Nonpolyposis Colorectal Cancer

Hereditary nonpolyposis colorectal cancer (HNPCC) is the most common of the inherited gastrointestinal syndromes predisposing to colorectal cancer. The syndrome accounts for approximately 2 to 3 of all colo- rectal cancers (Westlake et al, 1991 Salovaara et al, 2000). HNPCC is an autosomal dominant heritable syndrome. Therefore, 50 of the children of an affected individual will develop the syndrome. The penetrance of HNPCC has been estimated to be between 80 and 85 (Lynch et al, 1983 Vasen et al, 1996) thus, not all affected individuals will develop cancer in their lifetime. HNPCC is characterized by early age at onset, excess synchronous and metachronous lesions, right-sided predominance, and extracolonic manifestations. The median age of diagnosis of colorectal cancer in persons with HNPCC is approximately 45 years. Although most patients present with right-sided colon malignancies, up to 40 of patients present with left-sided colorectal tumors. In patients with HNPCC, the risk of...

RNAi In Basic Cancer Research

The release of nearly complete human genome sequences and the identification of a large number of genes whose aberrant expression is associated with a variety of cancers by high-throughput genomic and proteomic approaches have provided both unprecedented opportunities and challenges for the development of new cancer therapeutics. For example, gene expression profiling using DNA microarray technology has identified distinct signatures of cancer gene expression that are associated with metastatic capacity and prognosis of cancer. Although the identification of a large number of genes that are up- or down-regulated in cancer has provided a large amount of information for both basic and clinical cancer research, it provides no information on whether the altered expression of a particular gene is the cause or a consequence of cancer. Because only the tumor-causing genes are the likely druggable targets, functional validation of therapeutic targets among these genes become a major challenge...

RNAi In Clinical Cancer Therapy

In concept, diseases such as cancer, which are characterized by overexpression or aberrant activation of specific oncogenes, are suitable candidates for nucleic acid-based gene-silencing therapies. Several nucleic acid drugs that are based on ODNs were under clinical trials and Vitravene (sodium fomivirsen) has been used for the treatment of cytomegalovirus (CMV) infection of the eye in clinics (2,3,5). Several ribozyme-based phase I II clinical trials are in early-phase of clinical evaluation for patients with breast cancer, colon cancer, and hepatitis (3). The problems of toxicity and poor clinical efficacy with antisense and ribosome molecules remain to be solved even after more than a decade of drug development attempts. Although the term RNAi was coined just 6 yr ago (23) and the application of siRNAs in mammalian cells was started only three years ago (27,28), RNAi is rapidly taking center stage of the development of nucleic acid-based therapeutics. siRNA-based biotechnology...

HSPs in cancer and their possible relevance to prognosis

Complex formation between p53 and HSPs has also been shown to occur in several human tumours. Davidoff et al. (1992) demonstrated p53 HSP70 complexes in breast cancer. The tumours investigated in this series have been described as primary invasive breast carcinomas. Unfortunately, no information is available from this study by Davidoff et al. (1992) about the relationship between the detection of these complexes and the invasive nature of the carcinomas. Perhaps the value of this approach may be diminished because Iwaya et al. (1995) state that only a part of the p53 pool may enter into complex formation with HSPs. Nevertheless, it is noteworthy that the expression of HSP correlated positively with oestrogen receptor expression and inversely with epidermal growth factor receptor expression (Takahashi et al., 1994). This suggests that changes in HSP expression could be one of the events associated with the progression of breast cancer. Elledge et al (1994) did...

Cancer Predisposition in BRRS

The risk of malignancy in BRRS is not well defined. Historically, there is no mention of cancer predisposition in early BRRS literature (8,31), as follow up of cases into adulthood is virtually never reported. However, once it was realized that CS and BRRS are allelic (34) (discussed later), this opinion has changed. In addition, the single largest study of genotype-phenotype correlation in patients with BRRS demonstrated a strong correlation between germline PTEN mutations and both benign (fibroadenomas) and malignant breast diseases in families with BRRS or CS BRRS overlap (families consisting of individuals who meet CS criteria in addition to individuals felt to have BRRS) (35). This finding solidified the recommendation that all patients with PTEN mutations, irrespective of phenotypic presentation, be screened for cancer in the same manner as a patient with CS, and led to the evolution of the concept of PHTS.

Screening and Cancer Control

This chapter focuses on the use of screening for cancer. Cancer is a leading cause of death worldwide, and in 2007 accounted for 7.9 million deaths (around 13 of all deaths), a figure that is predicted to rise to 12 million by 2030 (WHO, 2009). Screening represents a major part of the cancer control effort, particularly in developed countries. The Papanicolaou (Pap) test for the detection of pre-cancerous cervical lesions is the most widely used cancer screening test. It was developed in 1928 and is now available to women across the globe albeit with different technologies and test frequencies. Some cervical cancer screening programs now also incorporate DNA testing for human papillomavirus (HPV), the viral precursor to cervical cancer. Mammography screening was developed in the 1950s for early diagnosis of breast cancer and involves taking a low-energy X-ray of the breast which is then examined for signs of calcification or soft tissue masses. More recently, colorectal cancer (CRC or...

Provision of Cancer Screening Services

Most cancer screening across the world is opportunistic, but some countries have regionally or nationally organized programs, in which every stage of the screening process from the invitation to participate, to the follow-up of abnormal results is organized and monitored by a central body. Opportunistic screening is dependent on the individual requesting a screening test or the health-care provider offering it, whereas organized screening depends on databases with information on the target population from which invitations are produced automatically. Both systems have advantages and disadvantages, but in general, organized programs usually offer free or subsidized tests, are able to achieve greater coverage, and minimize social inequalities in access (although not necessarily in uptake), by making sure everyone in the population who is eligible is invited (Miles et al, 2004). However, they could be criticized for reducing the opportunity for patient-provider interaction to discuss the...

Adenoviral Retargeting For Cancer Gene Therapy

A gene therapy for various disease settings requires different selectivity and targeting, highlighting the importance of choosing the right strategy for successful gene therapy. In the field of cancer gene therapy, aggressively proliferating cells need to be killed or suppressed. This unique situation demands multiple levels of function in order to achieve a therapeutic effect. First, virtually all tumor cells must be killed because any remaining viable cancer cells would lead to tumor regrowth. Second, the cytocidal effect needs to be limited to cancer cells, except in limited cases where the payload gene possesses tumor selectivity. In most cases, the transgene used for cancer gene therapy is nonselective. Such nonselectivity indicates that specificity must be achieved at the vector level without impeding killing potency in order to develop clinically usable cancer gene therapy strategies (6,61).

Immune response to a cancer

There is some evidence that cancer cells have surface membrane antigens called tumour-specific antigens (TSA) or tumour-associated antigens (TAA) that are recognized by the immune system as non-self, and can elicit an immune response. Antibodies secreted by B-lymphocytes will coat tumour cells and with the help of complement and phagocytic cells can cause tumour cell destruction. CD8+ T-lymphocytes and NK cells can cause direct tumour cell killing, whereas CD4+ T-cells release cytokines to augment tumour cell killing by macrophages. The concept of immune surveillance as protection against cancer, whereby lymphocytes continuously check dividing cells for mutations and destroy unacceptable cells, has not been proved (Fig. 11.15).

Immunodeficiency and cancer

Immunocompromised individuals such as patients after radiotherapy or chemotherapy, transplant patients on immunosuppressive drugs or those with an AIDS are at an increased risk of developing cancer. The risk is particularly for lymphoproliferative and cutaneous malignancies, which Figure 11.15. Histological slide of a patient with cancer of the breast. Note the infiltration of lymphocytes both into the connective tissue surrounding the cancer as well as directly into the cancer itself. Figure 11.15. Histological slide of a patient with cancer of the breast. Note the infiltration of lymphocytes both into the connective tissue surrounding the cancer as well as directly into the cancer itself.

Immunodiagnosis of cancer

If tumour cells express surface membrane, cytoplasmic or secreted products of specific antigenicity and in sufficient quantities, it should be possible to detect these by developing monoclonal antibodies against them. Unfortunately these techniques have not yet reached widespread application in either screening for early cancer or follow-up of cancer. The three most commonly used antigens used for these purposes are prostatic-specific antigen (PSA), used for screening and follow-up of prostate cancer carcin-oembryonic antigen (CEA), used for follow-up of colon cancer and a-fetoprotein, used for diagnosis and follow-up of liver cancer.