Suppression of vincristine-mediated cytotoxic activity by mitoxantrone in human cell lines.
In the present study, we used different cell lines to determine the anticellular effect of a combination of mitoxantrone (MXT) and vincristine (VCR). In all the cell lines tested, most cells (approximately 90%) in cultures with VCR (0.01-1 microM) alone died in the 3 days following exposure, while those with VCR and MXT (0.1-1 microM) invariably survived much longer (6-9 days). Based on the MTT and the 3H-thymidine uptake assays, it was shown that the antagonistic effect of MXT was optimal at 0.1-1 microM and when applied simultaneously. Our results showed that neither modulation of drug accumulation nor inhibition of tubulin assembly could account for the antagonistic effect of MXT. Furthermore, the cytotoxic effects of VCR and/or MXT had no correlation with c-myc gene expression and DNA fragmentation was not observed. Flow cytometry revealed that while most cells (> 90%) exposed to VCR alone for 16-24 h were arrested at the G2/M phase, a fraction of cells were able to escape mitotic arrest when MXT was also present. These results suggest that the use of MXT in conjugation with VCR for the treatment of cancers should be applied with caution.
Department of Medical Research, Veterans General Hospital-Taipei, Taiwan, Republic of China.
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D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D053938:DNA Fragmentation; D004273:DNA, Neoplasm / Q000187:drug effects; D016259:Genes, myc / Q000187:drug effects; D006801:Humans; D008942:Mitoxantrone / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D013936:Thymidine / Q000493:pharmacokinetics; D014404:Tubulin / Q000187:drug effects; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay; D014529:Uridine / Q000493:pharmacokinetics; D014750:Vincristine / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000493:pharmacokinetics / Q000494:pharmacology
D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D004273:DNA, Neoplasm; D012333:RNA, Messenger; D014404:Tubulin; D014750:Vincristine; D008942:Mitoxantrone; D013936:Thymidine; D014529:Uridine