Abstract
Clinical drug resistance is a major obstacle to successful chemotherapy for cancer. When it occurs, resistance to a wide range of agents is noted. This clinical observation should not be confused with so-called "multidrug resistance," which is a laboratory-based phenomenon, whereby cross-resistance in experimental models to structurally unrelated compounds is seen and is due to increased expression of P-glycoprotein (PGP). In the majority of cases of clinical drug resistance in solid tumors it is likely that other factors will play a major role. These other factors can be defined as pharmacologic or cellular. Pharmacologic factors are those that prevent an adequate degree of tumor cell exposure and include considerations of dose and schedule of drug, and also of drug metabolism, which may relate to concomitant medication and to genetic variations. Clinical maneuvers to circumvent drug resistance by increasing dose are so far of unproven value. Cellular factors are those that apply at the tumor cell itself, and it is probable that multiple mechanisms exist. These include considerations of drug uptake, activation/inactivation, and changes in target enzymes and in DNA repair processes. After DNA damage has occurred, a key determin...Continue Reading
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