Antineoplastic activity of mitoxantrone and its biological interactions in parental and multidrug resistant subline of P388 murine leukemia cells.
The antitumor effects of mitoxantrone (MITO) and the various mechanisms involved therein were investigated in the adriamycin sensitive (P388/S) and resistant (P388/ADR) P388 leukemia cells. Utilizing the MTT (3-[4,5/dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide) assay, MITO concentration less than 100 ng elicited 50% inhibition of P388/S tumor cell survival, while a 10 times greater dose of MITO was required to inhibit the P388/ADR cell survival by 50%. A MITO dose dependent inhibition of DNA, RNA and protein biosynthesis was observed in the sensitive cells, while MITO elucidated a negligible effect on the macromolecular biosynthesis in the resistant tumor cells. Induction of DNA strand scission was observed in P388/S cells exposed to 0.1 and 1 microgram/ml MITO, while a minimal formation of DNA lesions was evident in the P388/ADR cells treated with 5 micrograms/ml MITO. These strand breaks were found to be not associated with proteins in either P388/S or P388/ADR cells. Generation of free radicals due to MITO and formation of alkylating metabolites of MITO were found to be not involved in the cytotoxic response of MITO against P388/S and P388/ADR cells. MITO did not affect the glutathione based detoxification mechanism of the sensitive and resistant tumor cells. Results indicate that in spite of reduced intracellular drug retention and induction of DNA strand breaks in P388/ADR cells other hitherto unknown mechanisms besides DNA binding might be involved in the antitumorigenic potential of MITO.
Chavan
S
S
Chemotherapy Division, Cancer Research Institute, Tata Memorial Center, Parel, Bombay, India.
Parekh
H
H
Chitnis
M
M
D000477:Alkylating Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001711:Biotransformation; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000096:biosynthesis / Q000187:drug effects / Q000378:metabolism; D004351:Drug Resistance; D004354:Drug Screening Assays, Antitumor; D016166:Free Radical Scavengers; D005978:Glutathione / Q000378:metabolism; D007941:Leukemia P388 / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D046911:Macromolecular Substances; D051379:Mice; D008942:Mitoxantrone / Q000493:pharmacokinetics / Q000494:pharmacology*; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000378:metabolism; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000187:drug effects / Q000378:metabolism; D013778:Tetrazolium Salts; D013844:Thiazoles; D014407:Tumor Cells, Cultured / Q000528:radiation effects
D000477:Alkylating Agents; D004273:DNA, Neoplasm; D016166:Free Radical Scavengers; D046911:Macromolecular Substances; D009363:Neoplasm Proteins; D012334:RNA, Neoplasm; D013778:Tetrazolium Salts; D013844:Thiazoles; D008942:Mitoxantrone; C022616:thiazolyl blue; D005978:Glutathione