ENHANCEMENT OF DOXORUBICIN CONTENT BY THE ANTITUMOR DRUG LONIDAMINE IN RESISTANT EHRLICH ASCITES TUMOR-CELLS THROUGH MODULATION OF ENERGY-METABOLISM

The effect of the antitumor drug lonidamine (LND) on respiration, aero bic glycolysis, adenylate pool, doxorubicin (DOX) uptake, and efflux i n DOX-resistant and DOX-sensitive Ehrlich tumor cells was investigated . The results may be summarized as follows: 1) In both types of cells, LND inhibited both respiration and glycolysis in a dose-dependent man ner and lowered the ATP concentration. The effect was more marked in c ells incubated in glucose-free medium; 2) LND raised, to a remarkable extent, the intracellular content of DOX in resistant and sensitive ce lls respiring on endogenous substrates because of reduced ATP availabi lity, whereas in glucose-supplemented medium, where both respiration a nd glycolysis contributed to ATP synthesis, the increase was lower; an d 3) when LND was added to DOX-loaded cells, it failed to significantl y inhibit DOX efflux because of time-dependent phenomena. These findin gs indicated that LND, a drug currently employed in tumor therapy, mig ht also be useful in reducing or overcoming multidrug resistance (MDR) of those cells with a reduced ability to accumulate and retain antitu mor drugs. BIOCHEM PHARMACOL 56;7:841-849, 1998. (C) 1998 Elsevier Sci ence Inc.