Resistance to the microtubule inhibitor podophyllotoxin: Selection and partial characterization of mutants in CHO cells
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Stable mutants two- to fourfold more resistant to the microtubule inhibitor podophyllotoxin (PodRI) have been selected in a single step in Chinese hamster ovary (CHO) cells. Mutants showing higher levels of resistance to the drug can be obtained in a second-step selection using the PodRI mutants (PodRII class). Prior treatment of cells with the mutagen ethylmethane sulfonate markedly enhanced the frequency of both PodRI and PodRII mutants in culture. The spontaneous rate of mutation of PodRI as determined by fluctuation analysis was found to be 1 - 2 x 10(-5) and 4 x 10(-7) mutations/cell/generation at 20 and 30 ng/ml podophyllotoxin, respectively. Somatic cell hybrids between PodRI x PodS and PodRII x PodS showed intermediate levels of resistance to the drug, indicating that the PodR phenotype behaves codominantly under these conditions. Cross-resistance studies with various PodRI and PodRII mutants show that they are not cross-resistant to other microtubule inhibitors, e.g., colchicine, colcemid, griseofulvin, vinblastin, that have been examined, or to a compound such as VP16-213, which is a podophyllotoxin derivative which lacks microtubule inhibitory activity. These results indicate that the lesion in PodR mutants is highly specific and probably does not involve a permeability alteration.
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