Resistance to anticancer drugs

In AML cells, ABCG2 is overexpressed however, the association between the expression and clinical resistance to anticancer drugs remains undetermined (81,82). The identification of functional sequence variation in the ABCG2 gene could also be of interest in the field of prognosis of disease. 

Keenan C, Thompson S, Knox K, Pears C (1999) Protein kinase C-alpha is essential for Ramos-BL 6 cell survival. Cell Immunol 196 104-109 Kelley SL, Basu A, Teicher BA, Hacker MP, Hamer DH, Lazo JS (1988) Overex3q>res-sion of metallothionein confers resistance to anticancer drugs. Science 241 1815-1818... 

Kelley SL, Basu A, TeicherBA, Hacker MP, Hamer DH, Lazo JS. Overexpression of metallothionein confers resistance to anticancer drugs. Science 1988 241 1813-1815. 

Major mechanisms of cellular resistance to anticancer drugs are depicted in Fig. 55.2. 

Exactly why some forms of cancer are more difficult to treat pharmacologically than others remains unclear. Differences in the biochemistry, genetics, and location of certain cancer cells may make them less sensitive to the toxic effects of anticancer drugs.6 Resistance to anticancer drugs... 

There are very few tumor types in which the use of chemotherapy can bring about prolonged survival, and possibly cure, for individual patients. The most common reason for this is the development of drug resistance within tumor cells. The laboratory study of resistance to anticancer drugs has resulted in the discovery of numerous mechanisms present within tumor cells that act to reduce their cytotoxic effects. However, the failure to translate this basic laboratory research into improved clinical outcome for patients remains one of the most pressing problems in contemporary cancer research. 

It is obvious, therefore, that the study of the development of resistance to anticancer drugs in the clinical setting is more complex than in the laboratory and that often resistance can only be measured indirectly. This is not to say that clinical studies of the importance of laboratory-derived drug resistance markers cannot be done. It may help to explain, however, why the results are often less than clear. 

Resistance to anticancer drugs is viewed as one of the most significant barriers to the effective treatment of malignant tumors. It is therefore not surprising that despite the difficulties previously mentioned, many studies have been and continue to be performed to determine the clinical significance of specific drug-resistance mechanisms. 

Lepper ER, Nooter K, Verweij J, Acharya MR, Figg WD, Sparreboom A (2005) Mechanisms of resistance to anticancer drugs the role of the polymorphic ABC transporters ABCB1 and ABCG2. Pharmacogenomics 6 115-138... 

Table VIII-1-3. Modes of Resistance to Anticancer Drugs...

DRUG RESISTANCE Membrane transporters play critical roles in the development of resistance to anticancer drugs, antiviral agents, and anticonvulsants. P-glycoprotein, which exports many chemotherapeutics from cells, is overexpressed in tumor cells after exposure to cytotoxic anticancer agents. Other transporters (e.g., breast cancer resistance protein [BCRP], organic anion transporters, and several nucleoside transporters) also have been implicated in resistance to anticancer drugs. 

C. Resistance to Anticancer Drugs Drug resistance is a major problem in cancer chemotherapy. Mechanisms of resistance include the following. 

Song S, Wientjes MG, Gan Y, Au JL. Fibroblast growth factors An epigenetic mechanism of broad spectrum resistance to anticancer drugs. P Natl Acad Sci USA 2000 97 8658-8663. 

Metallothionein expression in certain tumour cells has been associated with resistance to anticancer drugs. Increased resistance to chlorambucil occurred in cultured cells with a high concentration of cytoplasmic metallothionein (Endresen et al. 1983). Metallothionein inhibited hydroxyl radicalgenerated DNA degradation (Abel and Ruiter 1989). Satoh et al. (1994) showed that pretreatment of tumour-bearing ICR nude mice with zinc salts increased metallothionein content, both in normal and tumour tissues, with a marked reduction in the antitumour activity of cisplatin, Ad-riamycin , and melphalan. Metallothionein null cells have increased sensitivity to anticancer drugs (Kondo et al. 1995). 

Stubbs M (1998) Tumour pH. In Molls M, Vaupel P (eds) Blood perfusion and microenvironment of human tumors. Implications for clinical radiooncology. Springer, Berlin Heidelberg, New York, pp 113-120 Stubbs M, McSheehy PMJ, Griffiths JR, Bashford CL (2000) Causes and consequences of tumour acidity and implications for treatment. Mol Med Today 6 15-19 Sullivan R. Pare GC, Frederiksen LJ, SemenzaGL, Graham CH (2008) Hypoxia-induced resistance to anticancer drugs is associated with decreased senescence and requires hypoxia-inducible factor-1 activity. Mol Cancer Ther 7 1961-1973... 

Fig. 1. Survival curves of C127 cells transduced with a bovine papilloma virus alone (O) or bovine papillomavirus containing an hMT IIA gene construct ( ). Cells were treated for 72 h with the drugs and the number of cells determined by a colorimetric assay. (From Kelley et al. 1988, Overexpression of metallothionein confers resistance to anticancer drugs. Science 241 1813-1815)...

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