Differential effect of clofibrate on adriamycin cytotoxicity in P388 murine leukemia cells sensitive and resistant to adriamycin.
Clofibrate (CPIB), an antihyperlipidemic agent, was utilized as a drug response modulator to modify the cytotoxicity of adriamycin (ADR) in vitro in P388 murine lymphocytic leukemia cells sensitive (P388/S) and resistant (P388/ADR) to ADR. CPIB elicited concentration and time dependent DNA biosynthesis inhibition which was completely reversible up to the concentration of 0.0025% in P388/S. However, only a partial reversibility of DNA biosynthesis inhibition was observed in P388/ADR cells treated with 0.0025% of CPIB. In both P388/S and P388/ADR there was complete and irreversible DNA biosynthesis inhibition at CPIB concentration of 0.005%. These findings were further confirmed by tumorigenicity analysis. CPIB was ineffective in altering ADR cytotoxicity in P388/S cells. However, in P388/ADR, CPIB enhanced ADR cytotoxicity at the lower concentrations of ADR and decreased the cytotoxicity upon increase in ADR concentrations. The enhancement in ADR cytotoxicity by CPIB in P388/ADR was due to increased ADR accumulation which was absent in P388/S cells. The present findings suggest the utility of CPIB as a selective agent to circumvent ADR resistance and to reduce host toxicity due to the drug.
Chitnis
M
M
Cellular Chemotherapy Unit, Tata Memorial Centre, Parel, Bombay, India.
Parekh
H
H
Satyamoorthy
K
K
D000818:Animals; D002994:Clofibrate / Q000494:pharmacology*; D004273:DNA, Neoplasm / Q000096:biosynthesis; D004317:Doxorubicin / Q000378:metabolism / Q000494:pharmacology*; D004351:Drug Resistance; D007941:Leukemia P388 / Q000473:pathology; D051379:Mice; D008811:Mice, Inbred DBA; D014407:Tumor Cells, Cultured
D004273:DNA, Neoplasm; D004317:Doxorubicin; D002994:Clofibrate