Reversal of multidrug resistance of tumor cells

Drug resistance to chemotherapy is rapidly emerging. Resistance to one drug carries over resistance to unrelated anticancer drugs leading to multidrug resistance (MDR). A major factor of MDR is P-glycoprotein (P-gp) mediated ABC transport found in many eukaryotic cells. P-gp acts as a drug eMux pump . The mdr1 gene involved in P-gp 170 protein production is localized in the human chromosome 7 band p21.0 - 21.1. Point mutations alter cross-resistan ce patterns. A variety of stimuli increase the expression of the mdr1 gene: lowered extracellular pH, heat shock, arsenite, cytotoxic agents, anticanc er drugs, transfection with oncogenes, HIV-1, and UV-irradiation. An altern ative hypothesis to the efflux pump claims that P-gp modifies the intracell ular environment to reduce accumulation of anticancer drugs in cancer cells by creating ionic or proton gradients. Chemosensitizers that block P-gp dr ug extrusion are generally lipid-soluble at physiological pH, possess a bas ic nitrogen atom and at least two co-planar rings. P-gp blocking does nor d epend on drug chirality. This opens the way of treating P-gp related MDR wi th chiral versions of drugs relatively harmless in terms of side-effects. W e believe that resistance modifiers combined with cytostatics will chemothe rapeutically be more effective for cancer patients.