Drug Resistance

Many patients undergoing chemotherapy fail to re spond to treatment from the outset; their cancers are re-

sistant to the available agents. Other patients respond initially, only to relapse.

Cancers can be regarded as populations of cells undergoing spontaneous mutations. The population becomes increasingly heterogeneous as the tumor grows and increasing numbers of mutations occur. Tumors of the same type and size will vary in their responsiveness to therapy because of the chance occurrences of drug-resistant mutations during tumor growth.

Assuming the same initial drug sensitivity, smaller tumors are generally more curable than larger tumors because of the increased probability of drug-resistant mutations in the larger tumors. Therefore, therapy earlier in the course of tumor growth should increase the chance for cure. Combination chemotherapy is often more effective than treatment with single drugs. Tumors that are resistant to drugs from the outset will always have a largely drug-resistant population and will be refractory to treatment.

Many kinds of biochemical resistance to anticancer drugs have been described. The biochemical and genetic mechanisms of resistance to methotrexate are now known in some detail. Three major resistance pathways have been described: (1) decreased drug transport into cells; (2) an alteration in the structure of the target enzyme dihydrofolate reductase (DHFR), resulting in reduced drug affinity; and (3) an increase in DHFR content of tumor cells. The increase in DHFR content occurs through a process of gene amplification, that is, a reduplication or increase in the number of copies per cell of the gene coding for DHFR. Amplification of various genes may be a relatively frequent event in tumor cell populations and an important genetic mechanism for generating resistance to drugs.

Tumor cells may become generally resistant to a variety of cytotoxic drugs on the basis of decreased uptake or retention of the drugs. This form of resistance is termed pleiotropic, or multidrug, resistance, and it is the major form of resistance to anthracyclines, vinca alkaloids, etoposide, paclitaxel, and dactinomycin. The gene that confers multidrug resistance (termed mdr I) encodes a high-molecular-weight membrane protein called P-glycoprotein, which acts as a drug efflux pump in many tumors and normal tissues.

Possible biochemical mechanisms of resistance to alkylating agents include changes in cell DNA repair capability, increases in cell thiol content (which in turn can serve as alternative and benign targets of alkylation), decreases in cell permeability, and increased activity of glutathione transferases. Increased metallothionein content has been associated with tumor cell resistance to cisplatin.

Drugs that require metabolic activation for antitumor activity, such as the antimetabolites 5-fluorouracil and 6-mercaptopurine, may be ineffective if a tumor is deficient in the required activating enzymes. Alter natively, a drug may be metabolically inactivated by resistant tumors, which is the case with cytarabine (pyrim-idine nucleoside deaminase) and bleomycin (bleomycin hydrolase). Leukemias have been shown to develop resistance to l-asparaginase because of a drug-related induction of the enzyme asparagine synthetase.

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

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