[Molecular basis for resistance to anticancer agents and reversal of the resistance]

Abstract

The development of drug resistance and especially of multidrug resistance (MDR) is a serious problem during treatment of various malignant tumors. Overexpression of P-glycoprotein (P-gp) has been observed in various multidrug resistant cells. P-gp acts as an energy-dependent drug-efflux pump. We have shown that the expression of P-gp is closely related to clinical drug resistance in some type of leukemia. We have found agents that reverse MDR and elucidated the molecular basis for the reversal of MDR. Thymidine phosphorylase (dThdPase) is an enzyme involved in pyrimidine nucleoside metabolism, but little is known about its physiological functions. We purified dThdPase from human placenta, and isolated partial cDNA clones for dThdPase. Amino-acid sequences were deduced from nucleotide sequences of the longest clone (288 base pairs). This sequence was 100% identical to the sequence of platelet derived endothelial cell growth factor (PD-ECGF) (residues 149-244). dThdPase is one of the activating enzymes for fluorinated pyrimidines. The sensitivity of KB cells transfected with PD-ECGF cDNA to doxifluridine was considerably higher than that of non-transfected KB cells.