Malignant Melanoma Healed with Natural Therapies

How To Prevent Skin Cancer

How To Prevent Skin Cancer

Complete Guide to Preventing Skin Cancer. We all know enough to fear the name, just as we do the words tumor and malignant. But apart from that, most of us know very little at all about cancer, especially skin cancer in itself. If I were to ask you to tell me about skin cancer right now, what would you say? Apart from the fact that its a cancer on the skin, that is.

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How I Survived Malignant Melanom

By The Time You've Finished Reading How I Survived Melanoma Skin Cancer Seven Survivors Tell Their Stories. You'll Feel Like A New Person, with A New, More Positive Outlook! You will learn: 1. How do I know if I have melanoma? What are the signs and symptoms? I wanted to know why the doctor was so concerned when she looked at that little mole on my forearm. What was it that looked so sinister? How worried should I be? Was the doctor over-reacting? 2. What tests will the doctor carry out to see if I have melanoma? Will they be able to tell me on the spot if there is a problem? Or will I have to wait for days, fretting about whats going on? 3. How curable is melanoma? If they do tell me its melanoma, what exactly does that mean? Is it a death sentence? Will they tell me You have 12 months to live. Get your life in order and prepare for the worst.? 4. What are the stages of the disease? The reading Id done said that there were different stages of melanoma. What are the symptoms of each stage? What are the survival rates of each stage? If I had a later stage melanoma, wouldnt I know about it? Wouldnt I actually feel like I was sick? 5. How quickly does the disease progress or spread? Should I have gone to the doctor sooner? Id noticed the mole changing over about 3 months. Was this delay critical? 6. How is melanoma normally treated? Would I have to go through chemotherapy and radiation treatment? If so, for how long? What are the odds of curing the disease using these treatments? How extensive is any surgery likely to be? How big will the scars be? 7. What are the common side effects of the treatments? Would I lose my hair? Would I become sterile? What else could I expect? 8. What alternative treatments are available? Id heard of people going on special macro-biotic diets. Id seen lots of herbal remedies on the internet. Which of these are proven and documented, and which ones are snake oil? Is it possible to combine alternative treatments with surgical other western treatments? How do I find a doctor that is open to using both alternative and western treatments? 9. What are the latest treatments being developed, and who is carrying out clinical trials of these new treatments?

How I Survived Malignant Melanom Overview

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Is There an Association Between Levodopa Therapy and Melanoma

The connection between levodopa therapy, PD, and malignant melanoma has been a matter of debate for three decades. It originally derived from the biochemistry of the drug. Levodopa is a substrate for the development of dopamine, which, in turn, develops into neuromelanin in CNS nigral neurons. It is the dopaquinones derived from levodopa that are oxidized to form neuromelanin in these cells (126). Hence, it has been proposed that levodopa may also affect the activity of melanocytes in the skin, possibly promoting malignant transformation, although this connection has never been proven. In addition, it is now known that 70 of melanoma cases in the general population appear to be connected with a genetic mutation unrelated to PD. Thus, it would seem unlikely that there would be a connection between PD, lev-odopa, and melanoma. Nevertheless, reports of melanoma in patients treated in the 1970s led the FDA to require language in the package insert that cautions against the use of levodopa...

Mucosal Melanomasspecial Considerations

Mucosal melanomas of the head and neck are rare, with only about 1000 cases reported. Of more than 84,000 melanoma cases in the National Cancer Data Base, only 1.3 were mucosal, and 55 of that subgroup arose in the head and neck (15). The majority of head and neck mucosal melanomas are sinonasal in origin, and the others are primarily from the oral mucosa. Among the sinonasal tumors, 81 arise in the nose and 19 in the sinuses, although the size of some of these tumors makes it difficult to be sure of the site of origin. Most of the oral lesions arise from the hard palate and maxillary alveolar ridge. Melanomas arising in other head and neck mucosal sites such as the larynx, pharynx, and cervical esophagus have been reported, but are quite rare. A melanoma arising in the oropharynx is shown in Figure 3. The oral lesions are often detected by healthcare personnel as a dark spot in the mouth, but the sinonasal lesions are often only apparent after symptoms such as epistaxis or nasal...

Mcam Muc18 expression in melanomas

MUC-18 is a 113 kDa glycoprotein expressed on the cell surface. The gene MCAM encoding MUC-18 is a member of the immunoglobulin family. The MCAM glycoprotein is an adhesion molecule bearing homology to other cell adhesion molecules such as NCAM and ICAM and also to the DCC gene product (see page 177), as well as to MHC-2 and MHC-1. MCAM is found in some mesenchymal tissues, e.g. smooth muscle cells, endothelial cells and Schwann cells but not in epithelial or haemopoietic cells. MCAM is found consistently in mesenchymal neoplasms of both smooth muscle and endothelial origin and bears obvious relationship to malignancy with the exception that, although it is expressed consistently in neurofibromas and schanno-mas, it is not found in malignant peripheral nerve sheath tumours (Shih et al., 1996). Interestingly, MCAM is expressed in a subset of capillaries and tumour endothelia but it is not found in the endothelia of arteries or large veins (Sers et al., 1994). MCAM is not found in...

The MC1R and human pigmentation and skin cancer

In 1995 we showed that sequence variation at the MC1R was common in man and that particular variants were associated with red hair and ''pale'' skin (Valverde et al., 1995). Such individuals are characterized clinically by a tendency to burn rather than tan in response to UVR, and pale skin on sites protected from the sun (such as the buttock). This clustering of phenotypic characteristics is known to be associated with an elevated risk of most forms of skin cancer (Rees, 2002c). Red hair approximates to an autosomal recessive trait although the penetrance depends on which MC1R variants are present (typically penetrance is around 0.85). This bold statement ignores some of the subtleties of phenotype hair color changes with age from childhood through early and late adulthood, and different body sites frequently have different colored hair. Given that the MC1R is a determinant of pigmentary phenotype and that pigmentary phenotype is a risk factor for both melanoma and NMSC it is not...

Other genetic factors and skin cancer

An increasing number of studies have recently reported on associations between various candidate genes and skin cancer. Most plausible are reports of associations between genes involved in DNA repair and skin cancer. Patients with xeroderma pigmentosum (OMIM 278730), an autosomal recessive disorder characterized by mutation in one of a number of genes involved in nucleotide excision repair, have a grossly elevated risk of both melanoma and NMSC (often presenting in early childhood with multiple tumors). Various studies have recently reported associations between some of the genes implicated in xeroderma pigmento-sum and skin cancer (Dybdahl et al., 1999 Tomescu et al., 2001 Winsey et al., 2000), whilst other studies have reported on associations between polymorphisms in pathways that may play a role in oxidative damage control in skin in response to UVR (such as the glutathione transferases) (Lear et al., 1997 Ramsay et al., 2001) or skin immunity (tumour necrosis factor a) (Hajeer et...

MC1R and Skin Cancer Risk

Over the past decade, the link between MC1R alleles and skin cancer risk in European populations has been well established.13 However, there are conflicting data on the magnitude of the risk associated with each variant allele, as well as which cancer types (melanoma or NMSC) particular RHC alleles are associated with. These differences are most apparent for the low-penetrance r variants, or rare RHC alleles such as R142H and I155T. Inconsistencies between association studies may be due to the composition of the populations being examined, or a lack of statistical power in some smaller scale studies. A recent meta-analysis on the association of the nine most studied RHC variant alleles with melanoma used pooled data from 11 separate reports.218 This combined analysis confirmed the association of the common R variants R151C, R160W, and D294H with RHC and melanoma. In addition, there was a significant association between the less common D84E and R142H variant alleles (frequencies...

BMC1R and CDKN2A Familial Melanoma

Germline mutations in the tumor suppressor CDKN2A gene are high-penetrance risk factors for melanoma.13 The presence of MC1R RHC variant alleles in carriers of the CDKN2A mutations can increase the penetrance, reduce the age of onset and contribute to the development of multiple primary melanomas.369,386-390 Notably, one case report described an individual, carrying both CDKN2A mutations and homozygous for MC1R variant R151C, who was exposed to ionizing radiation and developed multiple melanoma on the exposed side of her body.391 Furthermore, both MC1R R and r variant alleles are able to increase the risk of developing multiple primary melanomas,279,392 independent of CDKN2A mutation status. 392

CMC1R and BRAF Mutant Melanoma

Another interesting influence of MC1R is on BRAF mutant melanoma susceptibility. A recent study found that germline MC1R variants, whether in the heterozygous or homozygous state, are strongly associated with somatic BRAF mutations in CSD melanoma.378,393 Another study combined two previously analyzed data sets to gain more statistical power and confirmed that MC1R was associated with BRAF mutant melanoma. However, in contrast to the previous findings, this association was independent of CSD.394 The mechanism underlying the increased susceptibility of MC1R variant allele carriers to melanomas harboring BRAF mutations is unknown however, it could be due to the generation of ROS in MC1R variant carriers182 or may be independent of pigmentation phenotype. Although it seems that MC1R may be directly involved in susceptibility to melanoma, somatic alterations in the MC1R gene are not observed in melanoma

Melanoma

Rates of melanoma vary widely geographically, with the major determinant of risk being skin color. The relative incidence of subtypes of melanoma differs across racial groups with one rare subtype termed ''acral lentiginous melanoma'' occurring in all racial groups (Hudson and Krige, 1993 Stevens et al., 1990 Jimbow and Kukita, 1984) but the commoner subtypes (superficial spreading melanoma, nodular melanoma and lentigo maligna) occur essentially only in white persons. For these latter subtypes and among white populations, the highest incidence is in countries nearest to the equator, leading to the hypothesis that sun exposure is the major environmental determinant of melanoma risk (Armstrong, 1988). Australia and New Zealand have the highest rates worldwide (Jones et al., 1999 Parkin et al., 1997). Variation in skin color explains much of the variation within and between geographical locations. For instance, in Hawaii, the melanoma incidence rates for people of European descent are...

Skin cancers

There are two main types of skin cancer melanoma, arising from the neural crest derived melanocytes and basal cell carcinoma and squa-mous cell carcinoma derived from keratinocytes (the latter two referred to as non-melanoma skin cancer, NMSC) (Rees, 2002b). This broad distinction into two types is useful NMSC is extremely common and case-fatality extremely low (< 0.5 ) melanoma by contrast is less common but with a case fatality of -20 (Rees, 1998). Melanomas usually present as pigmented lesions with a darkening and increase in size of a preexisting melanocytic nevus (a benign collection of immature melanocytes) or de novo, as a lesion resembling a mole that is growing and getting darker. Melanoma may metastasize early and fatality is usually due to secondary spread. Because therapy of the tumor once spread has occurred is largely palliative, emphasis has been on primary prevention, early detection and excision of malignant lesions, and identification of high risk groups (Rees,...

Molecular Correlates Of Germ Cell Tumor Development And Function In Humans

C-Kit is a transmembrane glycoprotein (molecular weight, 145Kd) produced by the c-kit gene and is a member of the receptor tyrosine kinases. It is related to the receptors for platelet-derived growth factor, macrophage colony-stimulating factor, and the flt 3 ligand.70 In mice, its natural ligand is the Steel factor or the stem cell factor, and murine studies suggest that the function of Kit tyrosine kinase is important in the development of the interstitial cells of Cajal, mast cells, and normal hematopoiesis71 and in the development and maturation of spermatogonia.43 Curiously, c-Kit expression or mutation has been observed in a range of human malignancies, including mast cell leukemia, gastrointestinal stromal tumors, melanoma, and seminoma.7,72,73 Tian and colleagues7 found activating mutations of c-kit in about 10 of seminomas but in no instances of NSGCT, but it should be noted that these workers studied only exons 11 and 17. The commonality of c-kit mutations in melanoma, GCTs,...

Chromosomal abnormalities in cancer

Chromosomal and DNA ploidy is an important parameter which has served as a marker of prognosis in breast cancer (Hedley et al., 1987 Clark et al., 1989 Ferno et al., 1992 Grant et al., 1992 Wenger et al., 1993), as well as in other forms of cancer such as pancreatic adenocarcinoma (Porschen et al., 1993), melanoma (Karlsson et al., 1993), endometrial cancer (Rosenberg et al., 1989), and gastric leiomyosarcoma (Suzuki and Sugihira, 1993). An image cytometric study carried out in the authors' laboratory on breast cancer aspirate cells has also revealed a highly significant relationship between ploidy and prognosis (see Table 2) (G. V. Sherbet et al., unpublished data). Nevertheless, it should be noted that a dissenting view has been expressed with regard to the significance of aneuploidy as a prognostic indicator (Lanigan et al., 1992 Lipponen et al., 1992). Aneuploidy may be a consequence of cells entering the S-phase of the cell cycle prematurely. This can be inferred from the close...

Genetic instability and the generation of metastatic variants

Cifone and Fidler (1981) found that the rates of mutation to ouabain and 6-thiopurine resistance were three to sevenfold greater in cells with high metastatic potential than in cells with low metastatic potential. This study also contained two clones, differing markedly in metastatic ability, derived from the same tumour. The rate of generation of ouabain resistant mutants in the metastatic clone was 4.6-fold greater than in the low metastasis clone, suggesting that the highly metastatic clone was more unstable than the clone with low metastatic ability. These data have been supported by the rates of generation of drug-resistant mutants in Bl6 murine melanoma cell lines with different metastatic potential. The high metastasis variant, F10, has been reported to show a fourfold greater rate of generation of methrotrexate- and PALA-resistant mutations than the low metastasis variant F1 (Cillo et al., 1987). The rate of generation of EMS (ethylmethane sulphonate> induced...

DNA repair and repair fidelity in metastatic variants

The recognition and repair of DNA damage occurs before the cells enter the S-phase of the cell cycle and cells are held in the G phase until the repair process is completed. This checkpoint control is exercised by the nuclear phosphoprotein p53 whose levels increase when any damage to the DNA is sustained (see page 28). Defects in DNA damage repair are often encountered, e.g. as seen in the human autosomal recessive disorder xeroderma pigmentosum (XP), which are defective in their ability to repair u.v.-induced DNA damage (Lehmann and Nortis, 1989). Ataxia telangiectasia (AT) is another example of an autosomal recessive syndrome comprising progressive cerebellar degeneration, oculocutaneous telangiectasias and immune deficiencies. AT patients show high cancer incidence (Swift et al., 1991). Cell lines isolated from AT patients show hypersensitivity to ionising radiation and to radiomimetic agents this is believed to be due to defective DNA repair (Painter and Young, 1980). All the...

Genetic recombination in the generation of metastatic variants

Recombination ability of metastatic variants of the B16 melanoma. The pDR plasmid contains a selectable marker (gpt gene) and the neo (neomycin resistance) gene. The latter is present as two truncated, non-tandem but overlapping segments. The plasmid was transfected into the cells and transfectants were selected by growing the cells in XHATM culture medium, indicating gpt function. The transfectant clones were then expanded and subjected to selection for the presence of functional neo gene. Only those transfectants carrying stably integrated plasmid DNA, that have successfully recombined the neo gene fragments into a functional gene, will come through this selection procedure. This procedure allows one to determine the chromosomal recombination events occurring in these cells. Surprisingly, the ability of the low metastasis variant F1 to carry out chromosomal recombination was three orders of magnitude greater than the high metastasis variants BL6 and ML8. Extrachromosomal...

Frequency of HIT in Surgical Patients Treated with Porcine Mucosal UFH

Isolated limb perfusion (ILP) with melphalan employs extracorporeal circulation (and thus high-dose UFH) to treat melanoma or unresectable sarcoma limited to an extremity. In one study, HIT occurred in three of 108 patients (2.8 ), who also received sc UFH prophylaxis following ILP (Masucci et al., 1999). The occurrence of arterial thrombosis and partial limb amputation in two of these patients with HIT led the investigators to discontinue routine UFH prophylaxis post-ILP. The hypothesis that ILP is a high-risk situation for HIT was supported by a follow-up prospective study by these same investigators showing that heparin-dependent antibodies were formed in all nine patients who underwent ILP (despite not receiving postoperative UFH prophylaxis), with eight having strong antibodies that effected serotonin release in vitro (Masucci et al., 1999).

Risks of Other Cancers in BRCA1BRCA2 Carriers

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 3.5-fold risk of pancreatic cancer was also found, and significant excesses were also seen for cancers of the stomach, buccal cavity and pharynx, gallbladder and bile duct, and fallopian tube and for melanoma. A more recent study from the Netherlands also found increased risks of prostate, pancreatic cancer, and head and neck cancer (43).

Oncogenic Capacity Of The Jakstat Signaling Pathway

Extensive data describe activated Stat3 and Stat5 in tumors. Activating mutations of Stat3 and Stat5 and specific inhibition of Stat3 and Stat5 by gene deletion, antisense oligonucleotides, or dominant negative approaches have highlighted the importance of Stat3 and Stat5 in tumor formation. Mutations of Stat3 that allow spontaneous dimer-ization of the monomers in the absence of interactions between phosphorylated tyrosines and SH2 domains are sufficient to cause transformation and induce tumor formation in nude mice (98). Inhibition of Stat3 signaling using antisense Stat3 or by a Jak-selective tyrosine kinase inhibitor, AG490, restored the sensitivity of cells from patients with large granular lymphocyte (LGL) leukemia to Fas-mediated apoptosis (99). Downregulation of Fas correlates with an increase in metastatic potential and resistance of tumors to chemically and physically induced apoptosis. This effect is mediated, at least in part, by an interaction between Stat3 and c-jun,...

P53 cancer progression and prognosis

Cutaneous melanomas show marked p53 immunoreactivity (Bartek et al., 1991 Stretch et al., 1991 Cristofolini et al, 1993 McGregor et al, 1993). Cristofolini et al. (1993) also examined a series of 75 benign skin naevi and described 15 of these specimens as p53-positive. It ought to be pointed out, however, that the criteria for declaring specimens as positive for p53 staining vary considerably. Cristofolini et al. (1993) found less than 1 of cells composing the naevi stained for p53, but the melanomas contained a far higher proportion of p53-staining cells also six out of eight metastatic melanomas were p53-positive with up to 10 of cells staining for the p53 protein. McGregor et al. (1993) found malignant melanoma to be highly p53-positive with the majority of tumour cells (> 75 ) staining for p53. These authors regarded tumours with < 10 cells staining for p53 as weakly positive. It seems reasonable therefore to regard the Cristofolini series of benign naevi as weakly staining or...

From The Laboratory To The Clinic Oncolytic Herpes Simplex Viruses Appear Safe In Trials But Just How Effective Will

Adverse events, such as acute toxicity, viral shedding, clinically evident reactivation or encephalitis attributable to virus inoculation or replication were observed in either study at any of the doses, which escalated from 103-105 pfu with 1716 and 1 x 1063 x 109 with G207 (16,17). Patient deaths were primarily the reuslt of progressive cancer, with one report of radiation necrosis. Two of the G207 treated patients were alive as of December, 2003 (77). In addition, both studies were unable to establish a maximum tolerated dose (16,17). More recently, evidence has been obtained that is reportedly consistent with replication of 1716 within tumor samples over time, supporting the concept of tumor destruction by viral oncolysis (78). Finally, multiple injections of 1716 directly into skin lesions of a limited number of melanoma patients have proceeded without any harmful effects (79). A phase Ib II study involving G207 is currently underway open to patients with recurrent glioblastoma...

Subcellular localisation of p53 protein

Be exclusively nuclear or cytoplasmic, or a mixture of both (Faille et al, 1994). Non-Hodgkin's lymphomas show virtually exclusive (90 out of 96 samples) nuclear staining (Pezzella et al, 1993a). Its localisation in breast cancer was described as predominantly cytoplasmic (Horak et al, 1991). Both the nucleus and the cytoplasm may be stained in melanomas (Weiss et al, 1993 Parker et al,, 1994a). In the light of the interactions of p53 with cellular proteins (see page 31), it seems likely that the subcellular localisation patterns seen in tumours might be suggestive of the pathways by which wild-type and mutant proteins might be functioning. Moll et al (1992) carried out sequence analysis of p53 cDNAs from breast cancers showing cytoplasmic staining and found wild-type alleles in six out of seven specimens. In contrast, where nuclear staining of p53 was encountered, missense and nonsense mutations were found. Furthermore, a sample of normal lactating breast tissue also showed...

Intratumoral Gene Delivery By Alphavirus

Alphavirus vectors have been applied for several studies in tumor animal models. In this context, SFV particles expressing the p40 and p35 subunits of the murine inter-leukin-12 (IL-12) gene were injected into mice bearing B16 melanoma tumors (32). The tumor development was followed by Doppler ultrasonography and demonstrated a significant tumor regression as well as inhibition of tumor blood vessel formation. It was also shown, that repeated injections improved the tumor regression efficacy. In another study, significant regression of P185A tumor growth was achieved after intra-tumoral injections with SFV-IL-12 vectors (33). The size of the tumor played an important role in relation to efficacy as treatment of large tumors was less successful. The intratumoral injections also presented prophylactic efficacy, as long-term immunity and absence of reoccurrence of tumors were achieved.

Tumor Targeting Of Alphavirus Vectors

Yet another approach to obtain tumor selective transfection was attained by encapsulation of recombinant SFV particles in liposomes (40). By this procedure, targeted gene delivery to human LnCaP prostate tumors implanted in severe combined immunodeficiency (SCID) mice was achieved after systemic delivery of encapsulated SFV-LacZ particles. Systemic administration of encapsulated SFV particles expressing the p40 and p35 subunits of IL-12 to SCID mice with human Panc-1 pancreatic tumors resulted in statistically significant reduction in tumor growth after a single injection (41). Furthermore, an initial phase I study on advanced melanoma and kidney carcinoma patients demonstrated the safe use of this SFV vector in humans. In this study the maximum tolerated dose (MTD) for encapsulated SFV-IL-12 particles was 3 x 109 particles m2, which might seem relatively low compared with doses for other viruses, usually administered in the range of 1011 particles. However, in this case the dose is...

Prototypes Creating Representations of Illness and Targets for Management

Representations are dynamic a sore blemish on the skin may transform from an infection to a skin cancer, and the type of cancer (basal cell versus melanoma) may change the meaning of the prognosis from life threatening to curable. Feedback from self-examination, social comparisons, and care-seeking can reshape illness and treatment representations. Representations are unstable and the instability of a dynamic process poses challenges for descriptive studies and interventions.

Examples Of These Models In

This case highlights the shortcomings of all the models when a family history falls outside the strict remit of the model. The family history depicted in the pedigree is strongly suggestive of a mutation in BRCA2 to the experienced clinician, given the additional prostate cancer and melanoma on a background of early-onset breast cancer and ovarian cancer. Both these types of cancer have been found to be associated with BRCA2 mutations rather than BRCA1 mutations in recent studies EMBRACE, unpublished, Thompson et al. (37) . Out of the models above, only the Manchester scoring system and BOADICEA consider the additional cancers, and neither of them incorporates melanoma into their calculations yet. It is unexpected that the Myriad risk assessment for this family is identical to that for the family in Pedigree 1. This reflects the limitations of that model in terms of the number of relatives it assesses and the cancers it will consider. This pedigree also serves to demonstrate further...

Hydroxylation by monophenol monooxygenase

This type of reaction usually forms catechols from phenols. Its physiological importance in vertebrates is the formation of l-dopa from l-tyrosine by tyrosinase, usually in skin l-dopa is the precursor of melanin. The presence of unusually high urinary concentrations of intermediate metabolites associated with melanin formation is observed (in man) both after exposure to sunlight, and in patients with melanoma without exposure to the sun. These metabolites can be used as a marker in the diagnosis of melanoma. In mouse pups devoid of tyrosine hydroxylase tyrosinase appears to be responsible for the appearance of significant amounts of neural catecholamines K89 .

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...

Tyramine 3hydroxylase

Vibrio tyrosinaticus is composed of two tyrosinases, molecular weights 41 000 and 38 500 it does not cross-react with antiserum to hamster melanoma tyrosinase. It acts on l-tyrosine and slightly on the d- isomer and m-tyrosine, but catechol and l-phenylalanine are not substrates. It is inactivated by diethyldithiocarbamate, and this is reversed by Cu2 + , Mn2 + , Cd2+ or Fe2 + A141 .

Psychological Well Being and Health Behaviors

Studies of the relationship between positive well-being and healthy behavior choices have generated rather variable results. Although positive affect and more enduring traits such as life satisfaction have been associated with greater physical activity, not smoking and moderate alcohol consumption in some studies (Dear et al, 2002 Patterson et al, 2004 Schnohr et al, 2005), other investigations have generated null or even reverse results (Diener and Seligman, 2002 Graham et al, 2004 Murphy et al, 2005). Rather less is known about the associations between well-being and other health behaviors such as dietary choice. We carried out an analysis of the relationship between life satisfaction and seven health behaviors using data on more than 17,000 young adults in 21 countries (Grant et al, 2009). Greater life satisfaction was consistently associated with a reduced likelihood of smoking and with an increased rate of regular exercise in all the regions of the world that were tested,...

Molecular Chemotherapy With rAAV

Consideration of molecular chemotherapy strategies for selective killing of tumor cells suggests that long-term expression of transgenes is not an imminent requirement hence, AAV-based vectors are less preferred over adenoviral vectors. Further, the efficacy of adenoviral infection in different tumor cells has been reported to be significantly higher than many other available gene therapy vectors. However, it has recently been reported that the efficiency of rAAV transduction of primary tumor material, derived from malignant melanoma and ovarian carcinoma, is significantly higher (> 90 ) than that seen in established tumor cells of the same derivation in culture (86). This observation suggests that it is possible to utilize rAAV in direct targeting of tumor cells for an effective killing by approaches such as molecular chemotherapy, cytokine gene transfer, and inactivation of protooncogene expression. In addition, studies by Su et al. using an AAV-TK-IL-2 vector reported...

Mechanisms Of Invasion And Metastases

These various processes are under the genetic control of 'metastasis-promoting' genes which may have dominant positive effects. Metastases-suppressor genes also have been identified, of which nm23 on chromosome 17q has received particular attention. This gene, which was first isolated from murine melanoma cell lines of high metastatic potential, is closely homologous to a fruit fly gene associated with normal wing development. Its expression in human tumours interacts with aggressiveness.

Richard S Foster Md Richard Bihrle Md John P Donohue Md

What is sometimes underappreciated in regard to therapy for testicular cancer is that not only is metastatic testicular cancer chemosensitive, it is also surgery sensitive. The surgical removal of metasta-tic testicular cancer of the retroperitoneum, pelvis, lungs, mediastinum, or visceral organs is curative from 30 to 75 of the time, depending on the site of metastasis and the clinical situation. When one compares this ability to cure with surgical removal alone in cases of testicular cancer with the ability of surgical removal to cure in cases of other cancers (such as breast cancer, colon cancer, melanoma, etc), one can recognize that testicular cancer is unique from a surgical point of view. Furthermore, testicular cancer is amenable to surgical cure not only in patients at a low stage of disease but also in those patients who have completed chemotherapy or are resistant to chemotherapy. Even in the setting of chemorefrac-tory disease localized to the retroperitoneum, cure at the...

Response of kiplkip2 genes to antiproliferative signals

Macrophages exposed to mitogenic stimulation by colony stimulating factor 1, show Gj arrest upon cyclic-AMP treatment, and this block of proliferation is associated with an increase in kipl (Kato et al, 1994). Another instance is that of TPA which inhibits the growth of malignant melanoma cells and blocks GrS and G2-M transitions. In this tumour model, Coppock et al (1995) found high levels of wapl cipl and kipl in G, cells and these levels dropped as the cells entered the S-phase. This drop in the level of the cdk inhibitors could be prevented by treating the cells with TPA. Similarly, an increase in the levels of kipl and wafl cipl has been observed in the inhibition of proliferation of MCF-7 breast carcinoma cells (Watts et al., 1995). Interferon, which is a powerful antiproliferative agent causes G arrest of Daudi-Burkitt lymphoma cells, increases kipl expression, but does not appear to affect wafl cipl (Yamada H et al, 1995a). Conversely, cdk inhibitors are inactivated by...

Global Analysis of Gene Expression

In a few cases, it has been possible to confirm functional hypotheses first suggested by expression analysis. For example, the gene encoding RhoC (ARHC) was identified as an expression correlate of tumor metastasis in a melanoma model critically, blockade of RhoC diminished metastasis and activation enhanced metastasis in this model.57 As yet, few such functional hypotheses have been validated, due to the relative mismatch between our ability to rapidly generate such hypotheses using expression microarrays and our more limited ability to test them in the laboratory. However, methods for systematically testing gene function on a global scale are rapidly evolving and are discussed briefly in the next section.

Summary And Conclusions

Our studies and those of others (11, 25) indicated that IL-2R and endogenous IL-2 are ubiquitously expressed in human carcinomas both in culture and in situ. Data available from various laboratories provide evidence for the presence of IL-2R on melanoma cell lines and other tumour cell lines. Furthermore, the IL-2 IL-2R pathway appears to be operative in normal non-hematopoietic tissues, e.g., fibroblasts and keratinocytes (5, 26). Thus, this pathway appears to be active in vivo and in 6. Rimoldi D, Salvi S, Hartmann F, Schreyer M, Blum S, Zografos L, Plaissance S, Azzarone B, Carrel S. Expression of IL-2 receptors in human melanoma cells. Anticancer Res 1993 13 555-564 12. Alileche A, Plaisance S, Han DS, Rubinstein E, Mingari C, Bellomo R, Jasmin C, Azzarone B. Human melanoma cell line M14 secretes a functional interleukin-2. Oncogene 1993 8 1791-1796 29. Atkins MB. Interleukin-2 in metastatic melanoma establishing a role. Cancer J Sci Am 1997 3 57-58

Cancers Other Than Breast and Ovarian Cancer

Carriers families rectal Stomach bladder Pancreas Liver duct Uterine Pertonium tube Cervix Prostate Lymphoma cell skin Leukemia Melanoma combined Malignant Melanoma An increased risk of cutaneous malignant melanoma associated with having an affected family member was quantified (OR 2.69) in a study by Holman and Armstrong (124). It has been estimated that 8 to 12 of cases are attributable to inherited factors (11). There is a known association of malignant melanoma with a mutation in CDKN2 on chromosome 9 that codes for p16, another important regulator of the cell division cycle (125). Several studies have demonstrated an association of BRCA mutations and malignant melanoma. In 3728 individuals in 173 breast-ovarian cancer families with BRCA2 mutations, the BCLC (36) estimated a statistically significant RR for malignant melanoma of 2.58. However, a study by van Asperen et al. (126) noted no significant excess risk of malignant melanoma associated with BRCA mutations in first-degree...

Venous Thromboembolism

Venous thromboembolism (VTE) has long been known as a complication ofcancer. Venous thromboembolisms are usually divided into deep venous thrombosis (DVT) and pulmonary embolism (PE). When DVTs affect the proximal veins of the lower extremities they are usually treated as a PE. We discuss VTE with all brain tumor patients at the initial consultation. Mechanism of action for VTE includes, venous stasis (immobility), intimal injury, and alterations in coagulation. In brain tumor patients, Sawaya et al. (46) has shown alterations in the fibrinolytic system and an underlying coagulopathy as causes of VTE. Other associations include age, prior DVT, smoking, oral contraceptives, and obesity. During surgery, brain tumor patients often have induced dehydration and hyperosmolality that increase the VTE risk. Malignant brain tumor patients have also been shown to display an increased risk of VTE with reports of upward of 28 of patients having symptomatic events (47). At our institution we have...

Environment as determinant of i genotype and ii disease

First, within a long evolutionary sense, various regional differences in the biological attributes of human populations have arisen as a result of natural selection pressures exerted by local environments on human biology. In this sense, environment acts as a determinant of the local human genotype. Many examples are well known in the anthropological and biomedical literature. They include (i) variation in skin pigmentation, which (especially in today's world in which there has been considerable redistribution of regional populations over recent centuries) contributes to variations in local population risks of skin cancer and vitamin D insufficiency (ii) various enzymatic polymorphisms which are associated with altered risks of various diseases (e.g. the N-acetylation pathway enzymes, various of the cytochrome P450 oxidative enzymes, the activity of alcohol dehydrogenase, and lactase activity) many of which such polymorphisms are presumed to reflect the allele-selecting impacts of...

A2mtsl protein and HSPs in cell proliferation

Another cellular protein which appears to be associated concomitantly with both cell cycle progression and HSPs, is the 18A2 mtsl protein, a Ca2+-binding protein which is associated with the invasive and metastatic behaviour of cancer cells (see page 191). The cell cycle related expression of the 18A2 mtsl protein is now well documented. A high level of expression of 18A2 mtsl is invariably associated with large S-phase fractions in murine and in human carcinoma cells (Parker et al., 1994a Sherbet et al, 1995). Parker et al. (1994b) have further demonstrated, by means of gene transfer technology, that switching on the exogenous 18A2 mtsl in B16 murine melanoma cells induces them to undergo GrS transition, and it also appears to control the cell cycle traverse. In parallel, these studies have revealed an increase in the detectability of p53 protein (Parker et al, 1994a,b), suggesting that GrS transition may be induced by the sequestration of p53. The concomitant involvement of HSPs in...

Lymph node surgery in malignant disease

Tumour cells invade the venules and lymphatics in and around the primary cancer and also float down the draining veins and lymphatics. Most of these circulating cancer cells are destroyed, but some can develop into metastatic tumour in either lymph glands or distant organs. Metastatic spread is not in a centrifugal manner and local lymph nodes are often bypassed with metastatic deposits developing in more distal nodes. Tumour deposits in local lymph nodes are a clear indication of the metastatic potential of the primary tumour and in general are associated with an unfavourable outcome. A curative operation for a primary cancer aims to remove the primary tumour, surrounding tissue infiltrated by tumour and regional lymph nodes with metastatic deposits. Block dissection of uninvolved nodes do not improve outcome and are infrequently performed. In breast and melanoma surgery, new techniques are being developed to diagnose lymph node deposits in order to prevent unnecessary block...

Deregulated expression of bcl2 family genes in cancer

Primary tumours and their distant metastases follow similar or comparable kinetics of apoptosis. This may not be the case as shown by Matsuda et al. (1996). Primary and secondary tumours differ markedly in respect of the degree apoptosis. As expected, primary tumours show an inverse relationship between tumour growth and apoptosis but, in contrast, there is an increase of apoptosis in metastatic tumours. This should be taken as a note of caution in order to avoid over-interpretation of the state of expression of bcl-2 genes in tumours as independent predictors of their biological behaviour. Equally, high metastasis variants of the B16 murine melanoma have been reported to be more resistant to apoptosis than variants with low metastatic potential (Glinsky and Glinsky, 1996), and apoptosis index per se may also directly relate to patient survival (Aihara et al., 1995).

Studies to investigate genes and environment

The Melanoma Genetics Consortium (Bishop et al., 2002) examined the risk (penetrance) for melanoma among CDKN2A mutation carriers. Carriers of particular germline mutations in CDKN2A are known to be at increased risk of melanoma. In this analysis, based on families with multiple persons with melanoma and a germline CDKN2A mutation, the overall risk of melanoma was estimated to be 62 by age 75 years. However, there was statistical evidence of a difference with carriers in Australia having a risk higher than that of the USA which, in turn, was higher than that in Europe. In the general population, for comparable time periods, the risk of melanoma by age 75 was at its highest in Australia in which it approached 2 . On an age-specific basis, the population rates in Australia were approximately 7 times higher than in Europe, while the rates in USA were 5 times higher than those in Europe. With the limited precision of the estimates of the penetrance of CDKN2A in the published analysis, the...

Environment and high penetrance genes

Genes associated with high penetrance of cancer have been identified for breast cancer susceptibility (genes BRCA1, BRCA2 and TP53) (Chapters 15,16), colorectal cancer (APC germline mutations and mismatch repair genes, predominantly hMSH2 and hMLH1) (Chapter 17) and melanoma (CDKN2A) (Eeles et al., 2004). The risks of malignancy at one or more anatomical site are 0.60 or higher by age 75 years for mutations in each of these genes. Population-based studies suggest that approximately 1 in 500 of the general population carries a germline mutation in BRCA1 or BRCA2 (although some populations, such as Ashkenazim, have notably higher carrier frequencies. Carrier frequencies for germline mutations in the other predisposing genes may be marginally lower than for BRCA1 and BRCA2. Persons carrying such mutations represent a challenge for clinical management and an important group in which to examine the effects of environmental exposures as any exposures which are modifiable would be targets...

Other Clinical and Preclinical In Situ Cytokine Gene Therapy Approaches

Been inserted into a vaccinia virus that coexpressed the MUC-1 gene, which was then delivered as an intramuscular injection to men with advanced prostate cancer (73). No toxicity was observed and one patient that received three doses had some evidence of systemic immune effects. IL-15 was shown to contribute to the development of NK and antitumor response to prostate cancer in a xenograft model with PC-3 tumors (74). IL-18 may synergize with IL-12 (75) and although it has not been used in gene therapy strategies for prostate cancer the recombinant protein has been used in combination with IL-12 gene therapy in a bladder cancer model (76). The IL-24 gene also known as a melanoma differentiation associated gene 7 (MDA-7) has been used in preclinical studies for prostate cancer gene therapy (77).

Non Cancer Health Care and Health Maintenance

The transition off of primary cancer treatment is also a second opportunity to consider whether genetic assessment might be necessary. During an initial consultation, when taking the family history, a potential genetic predisposition may be detected. However, the patient may not pursue referral to a genetic counselor at that time because they are so overwhelmed by the new diagnosis of cancer and dealing with the treatment they will have to embark upon. The completion of treatment is another opportunity to review this issue and consider making a referral. The genetics of breast, ovarian, and colorectal cancers are best understood, but increasingly associations with other cancers such as pancreatic cancer and melanoma are being

Cytokine Modified Dendritic Cells

DCs are extremely efficient APCs that are widely dispersed in tissues and peripheral blood. Because they can be manipulated ex vivo and are perhaps the most specialized APCs they have been considered the prime candidates for cell mediated cancer therapy. A number of clinical trials using DC have been performed for prostate cancer (109-116) as well as other cancers (see ref. 117 for a review of the first 1000 trials). Although melanoma is the most commonly treated cancer using DC immunotherapy, GU cancers, notably, renal and prostate, are also being evaluated (118). Most of these studies involve DC primed with specific polypeptides that will bind MHC Class I or II molecules or with tumor lysates. Tumor derived mRNA transfected into DCs is being used to circumvent the challenge of lack of identity of TAAs. In current clinical trials DCs are most often injected intradermally or subcutaneously and less commonly intravenously or into a lymph node (118). A challenge with current clinical...

Gene Replacement Therapy

The protein product of the mda-7 gene, Mda-7 interleukin (IL)-24, is a novel cytokine that belongs to the IL-10 family of cytokines (40). Gene delivery using Ad-mda-7 results in growth suppression and apoptosis in a broad-spectrum of cancer cell types including those of the lung, prostate, mesothelioma, pancreatic, breast, gliomas, renal, and human melanoma (41-48). In contrast, Ad-mda-7 does not elicit deleterious effects in normal cells, including those of epithelial, fibroblast, astrocyte, melanocyte, or endothelial origin (49). Based on these distinctive properties and reports of antitumor and antiangiogenic activities in human tumor xenograft animal models, a The cyclin-dependent kinase inhibitor (CDK-I), p16, was identified in a yeast two-hybrid screen as a protein that inhibits the ability of cyclin-dependent kinase 4 (CDK4) and cyclin-dependent kinase 6 (CDK6) to regulate the phosphorylation status of phos-pho retinoblastoma (pRb), thereby controlling progression of cells into...

The Role Of Il11 In Tumour Metastasis

Human melanoma (A375M) and human breast cancer (MDA-MB-231) cells formed osteolytic bone metastasis in vivo when these tumour cells were injected into the left ventricles of BALB c nude mice (Figure 2) (17). These tumour cells promoted bone resorption in the in vitro neonatal murine calvaria organ culture system by indirectly stimulating the production of a bone resorption-inducing factor (or factors) from human osteoblast-like Saos-2 cells. In the course of examining the factors, we found that Saos-2 cells, in response to the interaction with tumour cells, produced a factor that promoted the proliferation of T10 cells. Because the T10 cell growth was IL-6 and IL-11 dependent (24), we checked the concentrations of both in the Saos-2-conditioned medium. We found that this conditioned medium stimulated the production of IL-11, but not IL-6, from Saos-2 cells. Furthermore, we found that a specific anti-IL-11, but not anti-IL-6, antibody could neutralize the abilities to induce T10...

Inhibitors of neovascularisation

Angiogenesis has provided a valuable target for developing anti-tumour agents. Earlier, we alluded to the binding of bFGF to heparan sulphate proteoglycans (HSPG) as a mechanism by which bFGF may be localised at the site of its action and protected from degradation. This has inevitably led to the use of heparinoids and related compounds to inhibit the heparin-binding growth factors. The polysulphonated naphthylurea suramin is a moderate inhibitor of these growth factors (Myers et al., 1991 Zugmaier et al., 1992). It appears to inhibit the binding of bFGF to endothelial cells (Takano et al., 1994). Suramin also inhibits VEGF and VEGF-induced chemotaxis of endothelial cells. The inhibition seems to result from inhibition of VEGF-mediated phosphorylation of the VEGF receptors (Waltenberger et al., 1996) possibly a mechanism by which suramin exerts its anti-angiogenic effect could be by interfering with the binding of angiogenic growth factors with their receptors. Braddock et al. (1994)...

Assay Techniques 41 Identification of VSMCs

It may also be appropriate to confirm that cultures are von Willebrand factor negative if there is concern about endothelial cell contamination (for example, when isolating VSMCs from small blood vessels). Separate markers have also been described for microvascular SMCs (pericytes) such as 3G5 43 , but there is debate about the specificity of this marker 44 . The high molecular weight melanoma-associated antigen is also a marker for pericytes in vivo 28 .

Cancer Surveillance And Prevention

Unfortunately there are no defined guidelines for screening or prevention for most LFS cancers. The most frequent tumors would be soft tissue sarcoma, osteosarcoma and brain tumors, none of which lend themselves to presymptomatic screening. New imaging techniques or serum proteomic discriminants are clearly needed. Given the lack of specificity for a distinct cancer type within a family, with the possible exception of adrenal cortical tumors, it is difficult to recommend aggressive screening. Patient education regarding symptoms, regular physical examinations with a physician aware of LFS risk and tumor spectrum, and application of noninvasive screening for melanoma and perhaps colon cancer (91) at an early age seem reasonable.

Alkylating Agent Resistance

The use of MGMT point mutants to differentially protect the hematopoietic compartment while sensitizing tumors has also been reported in animal xenograft models (126-128). Clinical trials using gene transfer of MGMT have been proposed by several investigators, and one phase I trial in patients with advanced malignancies such as melanoma, sarcoma and other solid tumors is in progress (129). The objective of this trial is to protect bone marrow stem cells from the toxic effects of chemotherapy and select for MGMT-G156A transduced cells during treatment. This strategy is expected to result in less toxicity to bone marrow and blood cells while enriching for the number

Management of the Unaffected Carrier

Carriers of BRCA2 mutations are also at risk of developing melanoma. Patients who have a family history of melanoma should be examined annually and advised to report any suspicious skin lesions. Those with a previous personal history of melanoma should be followed up regularly by a dermatologist.

Genetic Vaccines for Cancer Therapy

In patients with compromised immunity resulting from the progression of cancer and chemotherapy. Furthermore, the common requirement of multiple vaccinations can be problematic using viral vectors. Recently, it was shown that restimulation with adeno-virally transduced DCs actually decreased the antigen-specific immune response in favor of strong antiadenovirus specific immune reactions in melanoma patients (18). Pre-existing immunity can also inhibit delivery using viral vectors. Attenuated bacteria has also shown promise for vaccine delivery, but are associated with safety concerns as well (19).

Methods Of Dna Vaccine Delivery 31 Electroporation

Studies on the delivery of TAA antigens using electroporation have yielded promising results. Mendiratta et al. reported vaccination using electroporation with both plasmid encoded human GP100 and mouse TPR2 antigen elicited complete protection from melanoma challenge (21). Lohr et al. demonstrated that introduction of plasmid encoding IL-2 and IL-12 (inflammatory cytokine signals) by electroporation at tumor sites caused transduction and inhibition of murine melanoma without the systemic cytokine levels experienced after adenoviral gene transfer (22). Further investigations have shown that electroporation can be used to facilitate the discovery of novel antigen encoded plasmid constructs. For example, Kalat et al. used electroporation methods to optimize tyrosinase related protein-2 antigens to elicit CD8+ responses and inhibition of melanoma growth in two challenge models (23). This same group later demonstrated that electroporation was capable of inducing immune responses...

Vitronectin receptors

The expression of vitronectin, another adhesion-mediating glycoprotein, appears to be associated with glioblastomas but it was not detectable in normal glial cells or low-grade gliomas (Gladson and Cheresh, 1991). The progression of cutaneous melanoma appears to be associated with the emergence of the vitronectin receptor, avj 3 integrin. In MeWo human melanoma cells, retinoic acid has been shown to inhibit cell differentiation, increase melanogenesis and induce morphological changes, together with higher levels of vitronectin receptors (Santos et al., 1994). The emergence of the avj 3 vitronectin receptor in melanoma progression has also been described by Danen et al. (1994). These authors investigated a spectrum of cutaneous tissues including common naevocellular naevi, dysplastic naevi, primary cutaneous melanomas and metastatic melanoma. The vitronectin receptor was found to be associated only with primary melanoma and metastasis, but little is known to date regarding the...

Increasing Gene Expression

Replicons have proven to be powerful enhancements to DNA vaccination, and are capable of eliciting antibody and tumor protective responses at up to 1000 times lower titers than conventional naked DNA vaccines in a P-gal expressing tumor model (132). Vaccination with replicons has also induced protective immunity to melanoma challenge in a TRP-1 expression system, unlike conventional DNA vaccines (133). Although it is

Cloning With Cancer Cells

Cloning with cancer cells recently has been reported. Hochedlinger et al. (2004) reported that cloning with several types of cancer cells (leukemia, lymphoma, breast cancer) led to the formation of blastocysts, but not to development of inner cell masses (ICMs), the early progenitor of the embryo proper and ESCs. However, ESCs were established from clones made with nuclei from a RAS-inducible melanoma cell line, and these were subsequently used to produce chimeric mice using the tetraploid complementation method. The chimeric mice were predisposed to cancer, with an expanded spectrum of tumorigenesis. This result reveals that, although developmental pluripotency can be conferred upon cancer cell nuclei by the cloning method, the genetic factors that originally induced carcinogenesis predispose the clone to develop tumors of the same type as the donor, as well as other cell types that can respond to that genetic defect.

Clinical Manifestations Primary Lesion

A primary lesion is the most common manifestation of malignant melanoma of the head and neck region. This lesion can vary in appearance from the classical black-pigmented, raised lesion to an enlarging, skin-colored (amelanotic) mole (Fig. 1A and B). Melanoma can arise from a preexisting nevus or normal skin. The appearance of melanoma may be FIGURE 1 Primary melanoma has a wide range of appearances. (A) Superficial-spreading melanoma. (B) Amelanotic nodular melanoma of the scalp. (C) Lentigo maligna melanoma of the cheek. (D) Advanced cutaneous melanoma with satellite lesions of the scalp. Source Courtesy of Dr. Mark Faries. FIGURE 1 Primary melanoma has a wide range of appearances. (A) Superficial-spreading melanoma. (B) Amelanotic nodular melanoma of the scalp. (C) Lentigo maligna melanoma of the cheek. (D) Advanced cutaneous melanoma with satellite lesions of the scalp. Source Courtesy of Dr. Mark Faries. similar to other generally noninvasive skin cancers such as basal cell and...

Complications And Prognosis

The most important prognostic factors are primary tumor thickness, ulceration, and lymph node status. This is reflective of the AJCC TNM staging for melanoma (Table 1), where advancing stage corresponds with worsening prognosis (7). After biopsy and SNB, most patients can be given general prognostic counseling.

Virus Induced Changes In Mhc Class I Presentation Of Hostderived Peptides

Heat shock protein production is amplified during a variety of cellular stresses including viral infection. Therefore, an increase in intracellular HSP concentration may lead to increased MHC class I presentation of HSP-derived peptides. Infection of immortalized human T cells expressing HLA B*0702 with HIV increases intracel-lular levels of Hsp27. These increased intracellular levels of Hsp27 lead to increased presentation of the Hsp27-derived peptide APAYSRAL by the HLA B*0702 class I molecule (Hickman et al., 2003). The Hsp90-derived HLA B*1801 ligand EEVETFAF has also been observed following HIV infection (H.D. Hickman-Miller and W.H. Hildebrand, unpublished). Increased class I presentation of HSP-derived peptides is not limited to cells stressed through HIV infection. Hsp90 production is increased in HLA A*0201 homozygous cells following Epstein-Barr virus transformation while the class I HLA of melanoma cell line MelJuSo also present Hsp90p peptides when infected with measles...

VCAM1 in cancer invasion

The adhesion of human melanomas to endothelial cells occurs by a preferential recognition of VCAM-1 and is mediated by the integrin a4 , VLA-4 receptor (Rice and Bevilacqua, 1989 Martin-Padura et al., 1991). Invasive breast cancers invariably express ICAM-2 but show no detectable expression of ICAM-3 or VCAM-1 (Fox et al., 1995c). ICAM-1 and MUC18 (a melanoma associated antigen, see page 121) have been found in both benign and malignant cutaneous lesions but VCAM-1 occurs in 79 of benign skin naevi and in 62 of primary melanomas < 1.5 mm in depth compared with this, these ICAMs are expressed in only 6 of thicker melanomas. Also only 14 of lymph nodes metastases expressed VCAM-1 (Denton et al., 1992). These authors have suggested therefore that the loss of ICAM-1 may lead to reduced adhesion and may be conducive to greater metastatic spread of melanomas.

Targets for Antiangiogenic Antilymphangiogenic Gene Therapy 321 Inhibition of Proangiogenic Lymphangiogenic Growth

Simultaneously targeting VEGF production with antisense oligonucleotide and VEGF receptor signaling with receptor tyrosine kinase inhibitors enhances the anticancer efficacy of either therapy alone (96). Some focus has been given to the preclinical gene therapy with soluble truncated forms of VEGFR-2 (sVEGFR-2). This molecule functions in two ways by sequestering VEGF and, in a dominant-negative fashion, by forming inactive heterodimers with membrane-spanning VEGFRs (91,92). Recently, murine fibrosarcoma and melanoma cells transduced with a retrovirus expressing sVEGFR-2, showed tumor growth reduction by inhibition of angiogenesis however, it did not show

Dongchul Kang Zaozhong Su Habib Boukerche and Paul B Fisher

Expression occurring during induction of terminal differentiation in human melanoma cells treated with interferon-beta (IFN-P) plus mezerein (MEZ) (Figure 5). In RaSH, cDNA samples are restriction-digested with frequent cutters such as DpnII to an average size of 256 bp to improve hybridization efficiency. Moreover, restriction digestion of tester cDNA only prior to hybridization enables selection and cloning of tester-unique cDNAs by direct ligation of hybridization mixtures to corresponding sites in the plasmid vector. Thus, RaSH reduces the amount of starting materials required for conventional subtraction hybridization by one tenth by using PCR and obviates the need to separate and clone subtracted cDNA species into plasmid vector or bacteriophage, a nontrivial, technically demanding step in subtractive cDNA library construction (Jiang and Fisher, 1993 Sagerstrom et al., 1997). In addition, RaSH uses reverse Northern Blot hybridization for further rapid confirmation of...

The role ofselectins in cancer dissemination

Them to release factor which may in turn induce the expression of selectins by endothelial cells (Hakamori and Anderson, 1994). This would result in greater interaction and adhesion between tumour cells and the endothelial cells, thus facilitating the invasion of the microvasculature. Antibodies raised against E-selectin inhibit the adhesion of breast cancer cells to TNF-stimulated endothelial cells (Tozeren et al., 1995) and also inhibit invasion of endothelial cell layer in vitro (Okada et al., 1994). Interlukin-1 enhances the formation of lung colonies when A375M human melanoma cells are introduced into nude mice by the intravenous route. This increase in experimental metastasis is inhibited by antibodies to the IL-1 receptor (IL-r) and in vitro the IL-r antibodies have been found to inhibit the induction by IL-1 of E-selectin and VCAM-1 expression on endothelial cells (Chiviri etal, 1993). These findings argue strongly in favour of an important role for adhesion molecule in tumour...

Tumor Induced Changes In Mhc Class I Presentation Of Hostderived Peptides

Alterations in gene expression can induce changes in peptide presentation, including the expression of germ cell genes, often referred to as cancer-testis (CT) genes. Normally, these genes are expressed in the trophoblast and in testicular germ cells, which do not express MHC class I (Van Der Bruggen et al., 2002). Peptides novel to the mature immune system are presented on the MHC class I upon processing of the protein products of these genes. The function of most CT gene products is unknown but they are putatively involved in spermatogenesis. Their activation is likely due to genome wide demethylation seen in many tumors (Loriot et al., 2006). This extensive demethylation may be due to the loss or downregulation of DNA methyltransferases, as a result of transcriptional disregulation or mutation. These events open up the promoter regions of numerous genes that are normally transcriptionally repressed. The MAGE, BAGE, and GAGE families of CT genes were first identified in melanoma but...

E UVRInduced DNA Damage

A primary role of the melanin pigment in humans is to provide protection from UV-induced DNA damage in the cells of the skin. Melanosomes accumulate over the nucleus of keratinocyte cells, forming a nuclear cap, where melanin acts to absorb UVR.122 Although UV light generated by the sun is essential for vitamin D synthesis in humans, it is also the main environmental cause of skin cancer.1 Three bands of UV light have been classified UVA, which is made up of wavelengths from 315 to 400 nm UVB, which is made up of wavelengths from 280 to 315 nm and UVC, which is made up of wavelengths below 280 nm.123 UVC is totally absorbed by the Earths ozone layer and is therefore not involved in skin cancer formation,124 while UVA and UVB have both been linked to DNA damage and the formation of skin cancer.125 95 of the UVR that reaches the Earth's surface is UVA. Although only 5 is UVB, it is more cytotoxic and effective at inducing DNA damage and skin cancer.1 it is directly absorbed by DNA,...

Tumor Targeting 411 Transcriptional Targeting

Transcriptional targeting can be achieved by the use of an expression cassette which is activated by tissue specific promoters (TSPs) (167). The options are to use either a promoter with a high activity in tumor cells tumor ECs or to use inducible promoters to achieve therapeutic transgene expression. Examples of promoters with high tumor-selective activity (minimal expression in normal cells) are, CXCR4, cyclooxygenase-2 (COX-2), survivin (a member of the inhibitor of apoptosis protein family) and pre-proendothelin-1 (PPE-1) a precursor protein for endothelin-1. The human CXCR4 gene is expressed at high levels in many types of cancers, but is repressed in the liver. Thus, the CXCR4 promoter has a tumor-on and liver-off status in vitro and in vivo, which make it a good candidate TSP for targeted cancer gene therapy approaches, (i.e., for melanoma and breast cancers) (168). COX-2, a key enzyme in the synthesis of prostaglandins and thromboxanes, is highly up-regulated in tumor cells,...

The Discovery of MC1R and Its Role in the Regulation of Pigmentation

The melanocortin hormones with high affinity for MC1R include a-melanocyte stimulating hormone (a-MSH) and adrenocorticotropin hormone (ACTH), both of which are derived from the proopiomelanocortin (POMC) precursor through posttranslational cleavage.20 These peptides were known to be involved in a number of biological activities in the body including regulation of melanocyte growth and pigment production.134 a-MSH and ACTH were also known to bind to receptors that elevate cAMP levels135 and subsequently it was hypothesized by two groups that the a-MSH ACTH receptor or receptors would show sequence similarity to G-protein coupled receptors (GPCRs). Using PCR primers based on GPCR sequence homology and screening of candidate PCR products with a cDNA library constructed from melanoma cell lines allowed isolation of the full-length MC1R gene.136,137 The human MC1R gene encodes a 317-amino acid GPCR primarily expressed on cutaneous melanocytes.136,138,139 However, MC1R is not expressed in...

Urokinase in cancer invasion and metastasis

The topographical distribution of PAs in tumours has provided good reasons to believe that they assist the tumour in the invasion of neighbouring tissues. It was demonstrated several years ago that the metastatic potential of B16 murine melanomas can be modulated by altering the uPA activity associated with these cells, and the level of uPA activity of B16 cells was reported to be directly related to their ability to form pulmonary deposits (Hearing et al., 1988). An inhibition of the binding of endogenous PA to the PA receptors on the membrane can result in the inhibition of the invasive ability of tumour cells. Kobayashi et al. (1994) synthesised four Hachiya et al. (1995) have provided some experimental evidence in support of a role for the PAs in cancer invasion. These studies were carried out on the human breast cancer cell lines MCF-7 and MDA-MB-231 cells. The MDA cells produce more PA than the MCF-7 cells and, consistent with this, MDA cells have been found to be more invasive...

Stratospheric Ozone Layer

An intact stratospheric ozone layer (SOL) prevents excessive health-damaging ultraviolet radiation reaching the Earth's surface. Until the early 1970s this layer was intact (although there was a natural variation in the thickness of the SOL, depending on latitude, season and volcanic eruptions). The depletion of stratospheric ozone, first observed in the 1970s over Antarctica is primarily caused by the build-up of human-made ozone-destroying gases in the stratosphere, such as the chlorofluorocarbons (CFCs), and is causing an increase in ultraviolet irradiation (UVR) at the Earth's surface. Ambient terrestrial levels of UVR are estimated to have increased by over 10 at mid-to-high latitudes since 1980.49 In terms of the adverse effects on human health we can expect, for the first half of the 21st century, an increase in the severity of sunburn and the incidence of skin cancers in fair-skinned populations, and the incidence of various disorders of the eye (especially cataracts). Since...

Preliminary Evaluation Of Fnab Smears

Markedly cellular Favor malignancy Lymphoma Carcinoma Melanoma Sarcoma (rare) Moderately cellular Malignant (low cell yield) Lymphoma Carcinoma Melanoma Sarcoma (rare) Reactive Pediatric small round blue cell tumors Melanoma Sarcoma (rare) Malignant Lymphoma Carcinoma Melanoma Sarcoma (rare)

Obtaining Family History Information

Additionally, the pedigree should include information on all surgical procedures in affected and unaffected family members such as bilateral oophorectomy performed either for prophylaxis or for a benign condition or removal of skin lesions. Such surgeries may impact that individuals risk for cancer (as would be the case with oophorectomy) or may indicate another possible unsuspected cancer in the pedigree, such as a melanoma. An example of a cancer pedigree is presented in Figure 1 and important details of the family history are listed in Figure 2.

Alternative MC1R Signaling Pathways

TYR activity and melanin production does not always correlate exactly with cAMP accumulation,182 indicating that MC1R may signal via cAMP-independent pathways. Calcium responses have been seen for all the mouse melanocortin receptors (MCRs) including Mc1r183 as well as for MC1R in human melanoma cells.184 In addition, recent evidence suggests that transcriptional upregulation of TYR does not always occur in response to MC1R activation, and that the increase in tyrosinase activity in response to MC1R may be due in

Nora A Janjan John M Skibber Miguel A Rodriguez Bigas Christopher Crane Marc E Delclos Edward H Lin and Jaffer A Ajani

Other histologic subtypes include adenocarcinoma of the anus, small cell carcinoma, and melanoma. All of these histologic subtypes are associated with high rates of local recurrence and disseminated disease. A 1997 National Cancer Data Base report (Myerson et al, 1997) described the differences in anal cancer recurrence rates by histologic subtype and disease stage. Over one fourth of patients with adenocarcinoma develop distant metastases. The risk of local or distant recurrence was twice as high for squamous cell cancers as for adenocarcinomas, but the risk of distant metastasis was more than twice as high for adenocarcinomas as for squa-mous cell carcinomas (Table 16-1). The American Joint Committee on Cancer clinical staging system (Table 16-2) is the system most commonly used for carcinomas of the anal canal. Cancers that arise in the anal margin are staged according to the system used for skin cancers.

Overview Of Biomarkers

To compare the DNA-repair capacities of basal cell carcinoma (BCC) in skin cancer patients and controls (119). An age-related decline in DNA-repair capacity was detected, and reduced repair capacity was a particularly important risk factor for young individuals with BCC and for those with a family history of skin cancer. Younger individuals with BCC repaired DNA damage poorly when compared with controls. With increasing age, however, differences between cases and controls gradually disappeared (120). The normal decline in DNA repair observed with increasing age may account for the increased risk of skin cancer that begins in middle age, which suggests that the occurrence of skin cancer in the young may represent a biochemical manifestation of decreased repair capacity. The same technique has been applied in another case-control study (121) of 51 newly diagnosed lung cancer patients and 56 age-, sex-, and ethnicity-matched controls. The mean level of DRC in cases (3.3 ) was...

Dietary Prostate Cancer Risk Factors

Selenium is a trace mineral that has generated considerable interest as an anticancer agent. Like the carotenoids and vitamin E, selenium is a potent antioxidant, but it also has additional anticancer properties experimentally, including especially proapoptotic activity, although other mechanisms may also be involved.17 As with vitamin E, selenium was observed to reduce prostate cancer risk as an incidental finding in a clinical trial of secondary skin cancer preven-tion.18 In part because of its proven efficacy as an anticancer agent experimentally and because there are epidemiological biomarker data supporting selenium as a prostate cancer chemo-preventive agent, there are ongoing short- and long-term clinical trials to directly test the efficacy of selenium to prevent prostate cancer. Results of the short-term trials, which will evaluate the impact of selenium supplementation on the prostate cancer precursor lesion prostate in-traepithelial neoplasia (PIN) and on possible...

The role ofMMPs and TIMPs in cancer invasion and metastasis

A direct correlation between invasive and metastatic ability and the production of MMPs by cancer cells was documented several years ago. Type IV collagenase was shown to be associated with the degradation of basement membrane collagen and with the invasive and metastastic potential of tumour cells (Liotta et al., 1980 Turpeenniemi-Hujanen et al., 1985 Nakajima et al., 1987 Reich et al., 1988 Murphy et al., 1989). Cell transformation produced by exposure to chemical carcinogens has been known to produce alterations of stromelysin-2 gene transcripts (Matrisian et al., 1986a Ostrowski et al., 1988 Matrisian and Bowden, 1990). Transformation of cells with the H-ras oncogene has similarly been shown to result in the secretion of collagen type IV, together with the gain of metastatic properties (Collier et al., 1988). Oncogenic transformation by ras and myc genes often also generates phenotypes with metastatic ability, but this can be inhibited by the introduction of the E1A gene....

Sentinel lymph node biopsy

In recent years, sentinel lymph node (SLN) mapping and biopsy have been well established for intermediate to thick melanoma and clinically node-negative breast cancer. In a study of 114 patients (from Emory University School of Medicine) with thick melanoma (s4 mm), 32.5 had a positive SLN biopsy, half of which had a single-positive lymph node after dissection. The overall 3-year survival for SLN-negative patients was 82 versus 57 for node-positive patients.

Oncogenes and cancer metastasis

Davies BR et al. (1993) transfected rat mammary epithelial cells with p9Ka gene. The p9Ka-transfected cells produced tumours at a higher frequency, with a reduced latent period, and showed a higher incidence of metastasis than untransfected parental lines. We transfected its murine homologue, the 18A2 mtsl gene, placed under the control of the dexamethasone-inducible mammary tumour virus promoter into B16-F10 murine melanoma cells and demonstrated an increase in lung colonisation by the transfectant cells, when the transfected gene is switched on. In these cells alterations were seen in the cytoskeletal organisation of the cells accompanied by the accumulation of a greater number of cells in the S-phase fraction (Parker et al., 1994b). In both these studies the genes were transfected into either continuous cell lines or into transformed cells and it is suggested that these genes may be capable of altering the biological behaviour of cells only when they have undergone cellular...

Of In Vivo Activities

Treatment of highly accessible tumors for biopsy will definitely increase our knowledge of the in vivo activity of these genes. There is little technical difficulty in obtaining biopsies from superficial tumors, such as head and neck cancers, as well as melanoma. For tumors which post-treatment biopsy is prevented by technical and ethical reasons (e.g., brain tumors), applying gene therapy as a neoadjuvant therapy (i.e., given before operation) will allow us to analyze the biological endpoints from the resected tumors.

MC1R and the Red Hair Phenotype

Most individuals with the RHC phenotype are homozygous (R R) for the R alleles or compound heterozygotes for different variants (e.g., R r).8,220,221 The RHC phenotype does, however, occur in a small number of individuals heterozygous for variant alleles (R +), and there is also a significant heterozygote effect on skin photosensitivity,224 color, freckling,9,220,223,225 and melanoma risk.226

The ras oncogene in tumorigenesis

Increased ras expression has been described in several human tumours (Slamon et al., 1984 Spandidos and Agnantis, 1984 Viola et al., 1985,1986). Egan et al. (1987) subsequently showed that ras expression level correlated with metastatic potential in 10T1 2 and NIH-3T3 cells. The relationship between ras gene expression and cell transformation has been studied by several groups. The ras proto-oncogene and also the mutant forms of the gene can produce cellular transformation upon transfection (Egan et al., 1989). There are several other gene transfer experiments with ras (Chambers and Ling, 1984 Spandidos and Wilkie, 1984 Bondy et al., 1985 Pozzati et al., 1986 Collard et al., 1987a Chambers et al., 1990), which have generally supported its role in achieving neoplastic transformation. However, transfection of human melanocytes by ras does not produce the morphological and cytogenetic changes which are known to characterise melanoma in vivo (Albino et al., 1992). More recently Davies BR...

Local Delivery Of Herpes Simplex Virus Into Gliomas

Several different strategies have been applied to generate tumor-selective HSV-1 vectors, as first shown by Martuza et al. It appears that most oncolytic viruses may ultimately be targeting cells, which have altered signal-transduction pathways that promote tumorigene-sis. This can occur spontaneously as is the case for reovirus (10-12) or can occur by genetic re-engineering. In the latter case, mutations or deletions in the viral genome are commonly introduced to eliminate the expression of specific viral proteins, which renders the mutant vector dependent on the tumor cells for viral propagation. Some ofthese viral proteins are also associated with neurotoxicity and a dual beneficial effect is obtained by mutating these genes. One of these mutants (designated 1716) has progressed to phase 1 clinical trial in 2 studies which include 21 patients altogether (13,14). In both studies patients with recurrent malignant glioma, refractory to conventional therapy, were treated. The HSV-1...

Kelly K Hunt md and Rajagopal Ramesh PhD

The protein encoded by the melanoma differentiation-association gene 7 (MDA-7 IL-24) is a novel interleukin (IL)-10 family cytokine with unique tumor-specific apoptotic and antiangiogenic properties that make it especially attractive for use in cancer gene therapy applications. Mda-7 gene transfer with a replication incompetent adenoviral vector (Ad-mda7) induces apoptosis in a tumor specific manner, an effect that is independent of the status of other tumor suppressor genes, such as p53, Rb, or p16INK4. In addition to its direct cytotoxic effects, Ad-mda7 transduction causes secretion of a processed, glycosylated form of MDA-7 protein. MDA-7 is a novel interleukin (IL-24) with unique apoptotic functions. Studies on the secreted MDA-7 IL-24 protein have shown that it can act as a pro-Th1 cytokine, and induces secretion of interferon-gamma, tumor necrosis factor-a, IL-6, IL-12, and granulocyte macrophage colony-stimulating factor in human peripheral blood mononuclear cells . Additional...

Initial Identification and Characterization

The melanoma differentiation associated gene-7 (mda-7) was identified in HO-1 melanoma cells induced to terminally differentiate by treatment with fibroblast interferon (IFN- ), and the protein kinase C activator mezerein (MEZ) (1). The differentiated and growth arrested HO-1 melanoma cells mRNAs were used to generate a cDNA library another library was generated from proliferating HO-1 cells. Differentiation induction subtraction hybridization (DISH) of these two yielded a temporally spaced subtracted cDNA library enriched for genes activated during HO-1 terminal differentiation (2,3). The underlying hypothesis of the above approach was that cancer cells would stop or significantly reduce expression of genes regulating growth control or differentiation, and that treatment with IFN- and MEZ would reactivate them. mda-7 was identified as a gene with minimal or absent expression in proliferating melanoma cells, high expression in normal melanocytes, and inducible expression in terminally...

Spatiotemporal patterns of common skin diseases

The geographical prevalence of skin disease also varies greatly worldwide. Infection and infestations are especially common in many African countries and other third world nations. By contrast, skin cancer rates are low in those with black skin and highest in those of Northern European ancestry who now live in equatorial regions. Rates of the commonest skin cancers are 15-50 times higher in parts of Australia than in parts of the UK, in populations that largely share the same genetic ancestry (Holme et al., 2000 Rees, 1998 Rees, 2002b).

MDA7is an IL10 Family Cytokine

Chada S. et al. reported that exposure of melanoma cells to MDA-7 IL-24, induced secretion of interferon (IFN)-y and IL-6, but not of IL-4 or IL-5 in contrast, Ad-luc treatment did not induce IFN-y or IL-6, suggesting an MDA-7-specific effect (15). Transduction of these cells with Ad-mda7 induced increases in mRNA that mirrored the cytokine induction observed with exposure to the MDA-7 IL-24 protein. The report suggested that the effect was also specific to some types of tumor cells, because similar treatment of lung and breast cancer cells did not induce release of cytokines. Microarray analysis of non-small-cell lung carcinoma (NSCLC) cells transduced with Ad-mda7 corroborated the cytokine-like activity of this gene, and confirmed that MDA-7 can activate IFN-y and NF-kB signaling pathways. Given that IL-10 functions as an immunosupressive cytokine, and that it significantly inhibited MDA-7 IL-24 activity in human peripherral blood mononuclear cells (PBMCs), it is possible that mda7...

MDA7 is a Tumor Selective Apoptosis Inducing Factor

The initial observation of mda-7 loss of expression in melanomas and its correlation with progression of this type of tumors suggested growth suppressive properties in melanoma cells (4-7). Ensuing studies investigated the effects of ectopic expression of mda-7 in a wide variety of tumor cells (melanoma, carcinomas of the breast, colon, prostate, nasopharynx, high grade gliomas, and osteosarcoma) and proved that mda-7 inhibits tumor cell growth regardless of the status of other genes (p53, Rb, Bax or p16) (1,9,10) (see Fig. 2 for a representative study of lung cancer cells). However, expression of the gene in normal human skin fibroblasts and mammary breast epithelial cells did not significantly affect their growth or trigger apoptosis (9,10). Together, these reports indicate that MDA-7 is an IL-10 family cytokine with tumor cell apoptotic activity and that the cytotoxic effects it induces are specific to tumor cells (5,10,22-24). Several studies have investigated the signal...

Signaling Pathways Involved In Mda7 Mediated Tumor Cell Death

Induced apoptosis, although BAX and BAK were not upregulated. In all tumor cell lines tested, regardless of p53 status, the authors observed activation of caspases 3 and 9 and cleavage of PARP in tumor cells but not normal lung fibroblasts after Ad-mda7 treatment. Independent studies have also demonstrated up-regulation of p53, TRAIL, and DR4 after Ad-mda7 treatment. The antitumor effects were independent of the genomic status of p53, RB, p16, ras, bax, and caspase 3 in these cells (9,10,40). Normal cell lines did not show inhibition of proliferation or apoptotic response to Ad-mda7. Although mda-7gene transfer induced cell-growth arrest and apoptosis in a broad-spectrum of cancer cells, the underlying signals mediating cell death varied and were reported to be cell-type dependent. MDA-7 markedly activated pc-Jun and pATF-2 transcription factors in ovarian cancer cells after Ad-mda7 treatment. The downstream targets NF kB and AP-1 were both activated by Ad-mda7 at 24h. Activation of...

Direct Inhibitory Effects on Angiogenesis

Evidence for direct effect of MDA-7-mediated antiangiogenic activity in vivo was next examined. Subcutaneous implantation of MDA-7 producing 293 cells (293-mda7) mixed with A549 lung tumor cells (1 1 ratio) in nude mice resulted in significant suppression of tumor growth compared with tumor growth in mice implanted with a mixture of parental 293 cells and tumor cells (see Fig. 6). That the tumor growth inhibitory effects resulted from exogenous MDA-7 was demonstrated by detecting MDA-7 protein in the tumors. Note that A549 tumor cells do not express detectable endogenous MDA-7 protein. Tumor growth inhibition was demonstrated to occur via apoptotic death of tumor endothelial cells. Associated with tumor growth inhibition was a marked reduction in tumor vascular-ization as demonstrated by the reduced hemoglobin content, and less CD31+ endothelial cells (61). These results demonstrated the direct antiangiogenic activity for MDA-7 IL-24 in vivo. Although these experiments established the...

RolfF Barth Jeffrey A Coderre M Graga H Vicente Thomas E Blue and Shin Ichi Miyatake

Boron neutron capture therapy (BNCT) is based on the nuclear reaction that occurs when nonradioactive boron-10 is irradiated with low-energy thermal neutrons to yield high-linear energy transfer a particles and recoiling lithium-7 nuclei. Clinical interest in BNCT has focused primarily on the treatment of high-grade gliomas (HGG), and either cutaneous primaries or cerebral metastases of melanoma. Neutron sources for BNCT currently are limited to nuclear reactors and these are available in the United States, Japan, and several European countries. Accelerators also can be used to produce epithermal neutrons and these are being developed in a number of countries, but at this time none are being used for BNCT. Two boron drugs have been used clinically, sodium borocaptate (BSH) (Na2B12H11 SH), and a dihydroxyboryl derivative of phenylalanine, referred to as boronophenylalanine (BPA). The major challenge in the development of boron delivery agents has been the requirement for selective...

Antimetastatic Activity Of Mda7il24

Melanocytes, and mda-7induction in human hematopoietic cells after treatment with TPA. As mentioned above, mda-7 was initially inversely correlated with melanoma progression (10,22) which is consistent with our results demonstrating that MDA-7 protein expression localizes to superficial areas of primary cutaneous melanoma and decreases as one moves toward the deeper, more invasive, areas of the tumor (6,7). Taken together, these results strongly suggest that MDA-7 expression is lost during melanoma progression and invasion. MDA-7 has reportedly high levels of expression in melanocytes, and in early stage melanomas. Immunohistochemical (IHC) analysis done by our group on a group of paired metastatic and primary melanomas from patients confirms MDA-7 expression at variable levels, in approx 70 of primary tumors. MDA-7 expression significantly decreased in both percent of positive cells and intensity of expression at the deep invasive front of the tumor as compared with its corresponding...

Optimizing Delivery Of Boron Containing Agents

As shown in experimental animal studies (30,31,134-136), enhancing the delivery of BPA and BSH can have a dramatic effect both on increasing tumor boron uptake and the efficacy of BNCT. This has been demonstrated in the F98 rat glioma model where intracarotid (ic) injection of either BPA or BSH doubled the tumor boron uptake compared to that obtained by iv injection (30). This was increased fourfold by disrupting the BBB by infusing a hyperosmotic (25 ) solution of mannitol via the internal carotid artery. MST of animals that received either BPA or BSH ic with BBB-D were increased 295 and 117 , respectively, compared with irradiated controls (30). The best survival data were obtained using both BPA and BSH in combination, administered by ic injection with BBB-D. The MST was 140 d with a cure rate of 25 , compared with 41 d following iv injection with no longterm surviving animals (31). Similar data have been obtained using a rat model for melanoma metastatic to the brain. BPA was...

Exosomes As Immune System Regulators

Immunization efficiency with exosomes derived from dendritic cells, has began human evaluation (Escudier et al., 2005 Morse et al., 2005) and although a decrease in tumor has been observed owe to antitumoral response induction, is clear that obtaining exosomes from autologous DC is a complicated and impractical process. In contrast, the use of exosomes derived from tumor cells has proof to be useful choice to induce an effective antitumoral response in melanoma and murine plasmocitoma (Altieri et al., 2004 and personal observations). It might be a good alternative then for antitumoral induction if selective in vivo secretion of tumoral exosomes may be induced. In fact, exosomes derived from heat stress tumor cells contains higher concentrations of HSP70, induce a better priming of cytotoxic T lymphocytes (Dai et al., 2005), suggesting that presence of HSP70 is not only important for transport of immunogenic peptides through exosome structures but also during death of tumoral cells....

D MC1R Freckling and Nevi

Nevi are acquired long lasting benign pigmented lesions of the skin that have a clonal origin and a dermal component. The cells giving rise to these nests of melanocytes are unknown but they may possibly have a basis in the adult stem cells reconstituting the melanocytic pool of the epidermis. There are many different patterns of nevi and melanocytic growth and it may be expected that growth patterns observed should be a reflection of underlying genetic differences be they present naturally in the germline, such as pigmentation gene polymorphisms, or somatic mutations that commonly occur in the BRAF and NRAS oncogenes.397 Aberrant growth of melanocytic cells due to activation of proliferation or suppression of apoptotic pathways, resulting in dysplas-tic nevi, may play a part or be indicative of an increased risk of development of melanoma related to an increased mole burden. The density of nevi is highest during early adolescence, and surprisingly we have observed that those with red...

E MC1R and Melanocytic Morphology

A recent case report has highlighted a feature that may be underestimated in the diagnosis of melanoma the potential association of having white nevi lacking pigmentation and red amelanotic melanomas with MC1R status.398 Currently, it is unknown whether RHC variant alleles contribute to the development of this phenotype, but carriers of these variants may share characteristics of melanomas that lack significant pigmentation. This clinical observation is consistent with another recent report that has described preliminary investigations into the dermoscopic features of primary melanomas found during the examination of those in a high-risk CDKN2A mutation carrier Spanish population.399 Of nine patients included in this group, three were non-RHC carriers, three carried one RHC variant, and three were RHC homozygotes with red hair. Dermoscopic analysis found that the mean score of suspect melanocytic lesions (ABCD classification system) was significantly higher in noncarriers than RHC...

Chromosomal translocation in synovial sarcomas

A translocation t(X 18) (pll.2 qll.2) occurs consistently in synovial sarcomas. Several genes are located at the breakpoints in this translocation. They are SYT occurring on chromosome 18, and members of the testis cancer antigen SSX gene family, namely SSX1, SSX2 and SSX4 on the X-chromosome. The SSX genes are normally expressed in the testis and the thyroid. Of the SSX homologues, SSX J, SSX2 and SSX4 are frequently expressed in human neoplasms. SSX3 is not usually detected. Furthermore, SSX expression is found in many forms of cancer including breast cancer, colorectal cancer, head and neck tumours, melanoma and in lymphomas. No expression of the SSX genes is detectable in leukaemias, thyroid cancers, and seminomas (Tureci et al., 1998).

Cellular Delivery Methods

Another delivery method for both viral and non-viral vectors is ex vivo transduction of target cells that are then reintroduced into the patient (6). This delivery mechanism was first used by Rosenberg et al. in the initial human gene therapy trial when human tumor infiltrating cells were transduced with retroviral constructs and reinfused in metastatic melanoma patients (1). The advantage of this delivery method is that there is more control of the transduced cell and higher transduction efficiencies can be achieved in the target tissue. Disadvantages included difficulties in targeting the reinfused cells to specific anatomic locations as well as possible contamination with reintroduced biologic agents. Current research efforts are evaluating ex vivo transduction of stem and progenitor cells which may lead to more sustained gene expression and better tissue targeting.

Stimulating the Immune System

Antigens that are capable of provoking weak humoral or cellular reactions. By activating this immune response against tumor cells through gene transfer it is hoped that tumors can be eradicated either by the transferred gene product or activation of the patient's own immune system. In animal models, the administration of cytokines such as inter-leukin (IL)-2, IL-4, IL-6, IL-7, IL-12, tumor necrosis factor (TNF)-a, interferons and granulocyte macrophage colony-stimulating factor (GM-CSF) have resulted in tumor regression (8). The systemic administration of cytokines in human trials though has been limited by the severe toxicity of these cytokines. Gene therapy strategies offer an opportunity to overcome these limitations because of the potential for local delivery to injected tumor with reduction in systemic toxicity (9-11). Another approach to make tumor cells more immunogenic involves the cotransfer of stimulatory molecules such as B7.1 and B7.2. These molecules provide a key event...