Biology versus pharmacology in drug resistance (review)

Multidrug resistance has previously been considered mainly in a strictly pharmacological manner, based on the ability of the cells to eliminate and/or inactivate the cytotoxic agents and/or to modify the targets of their action. For example, attention has been drawn to drug transporters (P-glycoprotein, MRP, LRP) or to the behavior of DNA topoisomerases in tumor cells. However, these mechanisms need to be more completely validated in the clinic. More recently, the biological role of frequent genetic modifications, which are responsible for the oncogenic transformation itself, has been investigated. Oncogenes and factors such as p53 and the Bcl-protein family, implicated in DNA repair and induction/modulation of apoptosis, are now prominent in the mechanisms of drug resistance. Furthermore, certain cytokines (e.g. IL-6) and growth factors (EGF, IGF) may also be involved in MDR. On the other hand, some MDR tumors may exhibit collateral hypersensitivity to the cytotoxicity of other biological molecules (e.g. interferons, TNF, anti-Fas) or effector cells (CTL, NK). We review examples that indicate that a careful assessment of both pharmacological and biological variables in an individual tumor must be considered in the development of new appropriate strategies to overcome drug resistance.