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In Chinese hamster ovary cells, stable mutants that exhibit 250- to 350-fold resistance to camptothecin (Cpt^R mutants) have been isolated from mutagen-treated cultures. The Cpt^R mutants exhibited no cross-resistance towards drugs such as colchicine, vinblastine, taxol, or puromycin but showed slightly (2- to 3-fold) enhanced sensitivity towards various drugs that inhibit DNA topoisomerase II (namely teniposide, etoposide, doxorubicin, mitoxantrone, amsacrine, ellipticine), suggesting that the genetic lesion in these mutants was highly specific. In contrast to the wild-type cells, the Cpt^R line was resistant to camptothecin-induced DNA strand breaks as measured by alkaline elution. Biochemical studies revealed that in Cpt^R mutants the cellular activity as well as protein content of DNA topoisomerase I were reduced to about 40–50% of the level in wild-type cells. Normal levels of activity and content were observed for …