Verapamil reversal of vincristine resistance and cross-resistance patterns of vincristine-resistant Chinese hamster ovary cells.

The phenotypic properties of a large number of low-level vincristine (VCR)-resistant Chinese hamster ovary cell lines have been studied. In particular, we examined the correlation between the reversal of VCR resistance by verapamil (VRP) and cross-resistance patterns to other drugs. Cross resistance to other vinca alkaloids developed in parallel with VCR resistance. Doxorubicin resistance was observed in many of the cell lines, occurring even at the lowest levels of VCR resistance. Increased sensitivity to taxol (TAX) was a feature of half of the lines tested and there was no increased resistance to 5-fluorouracil or chlorambucil. Two main groups of mutants have been identified: (a) those that are thought to be membrane mutants which are cross-resistant to TAX and whose VCR resistance is reversible by VRP; and (b) those that appear to be tubulin mutants, which have increased sensitivity to TAX and resistance to VCR in the presence of VRP. It was not possible to distinguish between the different mechanisms of low-level resistance by drug accumulation studies in unsupplemented medium. However, VCR accumulation in the presence of VRP did correlate with the cross-resistance results.