SUPPRESSION OF VINCRISTINE-MEDIATED CYTOTOXIC ACTIVITY BY MITOXANTRONE IN HUMAN CELL-LINES

In the present study, we used different cell lines to determine the an ticellular effect of a combination of mitoxantrone (MXT) and vincristi ne (VCR). In all the cell lines tested, most cells (congruent to 90%) in cultures with VCR (0.01-1 mu M) alone died in the 3 days following exposure, while those with VCR and MXT (0.1-1 mu M) invariably survive d much longer (6-9 days). Based on the MTT and the H-3-thymidine uptak e assays, it was shown that the antagonistic effect of MXT was optimal at 0.1-1 mu M and when applied simultaneously. Our results showed tha t neither modulation of drug accumulation nor inhibition of tubulin as sembly 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 es cape mitotic arrest when MXT was also present. These results suggest t hat the use of MXT in conjugation with VCR for the treatment of cancer s should be applied with caution.