Chapter 36 : Mechanisms of Resistance to Anticancer Agents

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Drug resistance, either intrinsic or acquired, remains one of the primary causes of failure for cancer chemotherapy. This chapter focuses on alterations in the carrier mediated transport systems that are responsible for intrinsic and acquired resistance. As with the antifolate drugs, a single, or a combination of different, mechanism(s) can mediate resistance to nucleoside anticancer agents. Reduced cellular accumulation of anticancer agents is one of the most studied forms of multidrug resistance (MDR). In terms of cellular resistance to anticancer agents, at least 10 family members have been implicated in drug resistance (MRP1-7, MDR1, BCRP, and ABCA2), and four of these have been shown to generate a resistance phenotype in cultured cells. Resistance to several different anticancer agents that are substrates for glutathione-S-transferase (GST) is associated with increases in GST levels (e.g., chlorambucil, melphalan). Interestingly, increased GST levels have been shown to be associated with resistance to non-GST-substrate anticancer agents. Commonly used camptothecins include topotecan and irinotecan. Cell culture based experiments have elucidated several point mutations in the TopoI enzyme, which are responsible for resistance. It should be noted that mutations in TopoI produce resistance to a class of molecules but do not always grant cross-resistance to other TopoI inhibitors. A better understanding of the mechanisms operating at the clinical level is crucial for the development of drugs aimed at circumventing resistance or therapeutic regimens for preventing the emergence of resistance.

Citation: Draper M, Jones G, Gould C, Modrak D. 2005. Mechanisms of Resistance to Anticancer Agents, p 473-499. In White D, Alekshun M, McDermott P (ed), Frontiers in Antimicrobial Resistance. ASM Press, Washington, DC. doi: 10.1128/9781555817572.ch36
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Figure 1.

Overview of the basic mechanisms of resistance.

Citation: Draper M, Jones G, Gould C, Modrak D. 2005. Mechanisms of Resistance to Anticancer Agents, p 473-499. In White D, Alekshun M, McDermott P (ed), Frontiers in Antimicrobial Resistance. ASM Press, Washington, DC. doi: 10.1128/9781555817572.ch36
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Figure 2.

Chemical structure of folic acid (folate), a naturally occurring vitamin necessary for cells, presented opposite the anticancer drug methotrexate.

Citation: Draper M, Jones G, Gould C, Modrak D. 2005. Mechanisms of Resistance to Anticancer Agents, p 473-499. In White D, Alekshun M, McDermott P (ed), Frontiers in Antimicrobial Resistance. ASM Press, Washington, DC. doi: 10.1128/9781555817572.ch36
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Figure 3.

Chemical structures for clinically used nucleoside drugs.

Citation: Draper M, Jones G, Gould C, Modrak D. 2005. Mechanisms of Resistance to Anticancer Agents, p 473-499. In White D, Alekshun M, McDermott P (ed), Frontiers in Antimicrobial Resistance. ASM Press, Washington, DC. doi: 10.1128/9781555817572.ch36
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Figure 4.

Mutations in the topoisomerase I gene that result in increased resistance to drug.

Citation: Draper M, Jones G, Gould C, Modrak D. 2005. Mechanisms of Resistance to Anticancer Agents, p 473-499. In White D, Alekshun M, McDermott P (ed), Frontiers in Antimicrobial Resistance. ASM Press, Washington, DC. doi: 10.1128/9781555817572.ch36
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Figure 5.

Topoisomerase II mutations that result in increased drug resistance.

Citation: Draper M, Jones G, Gould C, Modrak D. 2005. Mechanisms of Resistance to Anticancer Agents, p 473-499. In White D, Alekshun M, McDermott P (ed), Frontiers in Antimicrobial Resistance. ASM Press, Washington, DC. doi: 10.1128/9781555817572.ch36
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