BIOLOGY VERSUS PHARMACOLOGY IN DRUG-RESISTANCE (REVIEW)

Multidrug resistance has previously been considered mainly in a strict ly pharmacological manner, based on the ability of the cells to elimin ate and/or inactivate the cytotoxic agents and/or to modify the target s of their action. For example, attention has been drawn to drug trans porters (P-glycoprotein, MRP, LRP) or to the behavior of DNA topoisome rases in tumor cells. However, these mechanisms need to be more comple tely validated in the clinic. More recently, the biological role of fr equent genetic modifications, which are responsible for the oncogenic transformation itself, has been investigated. Oncogenes and factors su ch as p53 and the Bcl-protein family, implicated in DNA repair and ind uction/modulation of apoptosis, are now prominent in the mechanisms of drug resistance. Furthermore, certain cytokines (e.g. IL-6) and growt h factors (EGF, IGF) may also be involved in MDR. On the other hand, s ome MDR tumors may exhibit collateral hypersensitivity to the cytotoxi city of other biological molecules (e.g. interferons, TNF, anti-Fas) o r effector cells (CTL, NK). We review examples that indicate that a ca reful assessment of both pharmacological and biological variables in a n individual tumor must be considered in the development of new approp riate strategies to overcome drug resistance.