Cross-resistance of vinblastine- and taxol-resistant mutants of Chinese hamster ovary cells to other anticancer drugs.

Stable mutants resistant to the anticancer drug vinblastine (VinR mutants) have been isolated after a single selection step from Chinese hamster ovary cells. Of the two types of VinR mutants which are obtained, one class exhibits specific cross-resistance to only some of the microtubule inhibitors. However, the second type of mutants, which is affected in membrane permeability, exhibits cross-resistance to a wide variety of unrelated compounds. Both classes of VinR mutants showed codominant expression in cell hybrids formed between resistant and sensitive cells. The cross-resistance patterns of the VinR mutants and a single-step mutant resistant to the anticancer drug taxol (TaxR mutant) toward various anticancer drugs have been determined. The mutants resistant to both of these drugs showed significantly increased resistance toward aclarubicin, dactinomycin, doxorubicin, bisantrene, bruceantin, chromomycin A3, demecolcine, colchicine, daunorubicin, ellipticine, emetine, ethidium bromide, maytansine, mithramycin, mitoxantrone, nitidine chloride, olivomycin, podophyllotoxin, puromycin, taxol, vinblastine, vincristine, vindesine, teniposide, and etoposide. Interestingly, either one or both of the above mutants exhibited somewhat enhanced sensitivity toward vidarabine, acivicin, bleomycin, cisplatin, cytarabine, alpha-difluoromethyl-ornithine, 5-FU, tegafur, and tiazofurin. For a number of other anticancer drugs which were examined (chlorambucil, mitolactol, IMPY, hexamethylmelamine, hydroxyurea, diglycoaldehyde, methotrexate, mitoguazone, mitomycin, nocodazole, and 6-thioguanine), the level of resistance of these mutants was found to be unaltered. The information regarding cross-resistance and collateral sensitivity patterns of VinR and TaxR mutants should prove to be very useful in the design of drug combinations which could prove more effective in cancer chemotherapy.