Clinical drug resistance: the role of factors other than P-glycoprotein.

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 determinant of the sensitivity of the tumor cell is its ability to undergo apoptosis. It is conceivable that failure to engage this process is a key factor in resistance to a number of drug classes, although there is little clinical evidence to support this at present. However, the genetic controls for the process of apoptosis are now being unraveled, and if this notion proves correct, the possibility will exist for the design of more rational means of circumventing drug resistance to a wide range of agents. In the meantime, strategies that should be pursued further in order to overcome this key clinical problem include further exploration of alternating or sequential drug schedules and using new non-cross-resistant agents, such as taxoids.