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Figure 20.9 Relationship between remission of a neoplasm and a complete cure as a function of the remaining numbers of neoplastic cells in the host. In this hypothetical example, treatment is initiated when there are about 100 g (1011 cells) present in the host. Each treatment, given at monthly intervals, eliminates 90% of the cells present, leading to complete disappearance of any clinical evidence of the neoplasm in the host or a "complete remission." However, more than 108 viable cells are present, many of which have now become resistant to the therapy utilized, with subsequent regrowth requiring alternate methods of therapy or ultimately leading to demise of the patient. Note that despite the attainment of a complete remission or clinical response, more than 108 viable neoplastic cells remain and that the reduction in cell numbers is small compared to that required for a cure. (Adapted from Tannock, 1992, with permission of the author and publisher.)

Figure 20.9 Relationship between remission of a neoplasm and a complete cure as a function of the remaining numbers of neoplastic cells in the host. In this hypothetical example, treatment is initiated when there are about 100 g (1011 cells) present in the host. Each treatment, given at monthly intervals, eliminates 90% of the cells present, leading to complete disappearance of any clinical evidence of the neoplasm in the host or a "complete remission." However, more than 108 viable cells are present, many of which have now become resistant to the therapy utilized, with subsequent regrowth requiring alternate methods of therapy or ultimately leading to demise of the patient. Note that despite the attainment of a complete remission or clinical response, more than 108 viable neoplastic cells remain and that the reduction in cell numbers is small compared to that required for a cure. (Adapted from Tannock, 1992, with permission of the author and publisher.)

mada et al., 1997; Baggetto, 1997). However, a variety of agents that are capable of modulating the function of the P-glycoprotein have been described (Kavallaris, 1997), but as yet it does not appear feasible to employ such agents together with the effective chemotherapeutic drugs that are transported by this protein.

Modified Availability of Drug Targets (Gene Amplification and Karyotypic Instability)

Some 25 years ago, Terzi (1974) pointed out that drug-resistant mutants of some cell lines were characterized by karyotypic instability, a high reversion frequency, and low plating efficiency. Subsequent studies have supported these initial observations in demonstrating alteration of response to drug therapy in cells by induced DNA rearrangements (Schnipper et al., 1989), hy-poxia-inducing genetic instability in neoplastic cells (Teicher, 1994), and the importance of tumor heterogeneity resulting from karyotypic instability in the response of neoplasms to specific drugs (Simpson-Herren et al., 1988). Another closely related mechanism of drug resistance was initially described by Schimke, who demonstrated that cells resistant to the antifolate meth-otrexate exhibited a dramatic amplification of the gene to which the drug dihydrofolate reduc-tase was targeted (Schimke, 1984). Subsequent to those studies, a number of examples of drug-induced gene amplification in karyotypically unstable cells have been reported (Table 20.7). In addition to the examples listed in the table, examples of induced gene amplification of topo-isomerase II by etoposide in human melanoma cell lines (Campain et al., 1995) and the amplification of metallothionein genes by metals (Gick and McCarty, 1982) and potentially by alkylating agents (Kelley et al., 1988) have been reported.

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