Characterisation of a human small-cell lung cancer cell line resistant to the DNA topoisomerase I-directed drug topotecan.
Camptothecins are DNA topoisomerase I-directed anti-tumour drugs with a novel mechanism of action. Topotecan (TPT), a hydrophilic derivative of camptothecin, is currently undergoing phase II clinical trials in small-cell lung cancer (SCLC). Human SCLC OC-NYH cells were made more than 6-fold resistant to topotecan by stepwise drug exposure and resistance was stable for 70 passages without drug. NYH/TPT cells had half the topoisomerase I level and activity of wild-type cells. However, no difference in camptothecin or topotecan inhibition of topoisomerase I-mediated DNA relaxation was found, indicating that the enzyme itself was unchanged in the resistant cell. In NYH/TPT cells, topoisomerase II alpha and beta levels were increased approximately 2-fold. Accordingly, the topoisomerase II-directed drug etoposide (VP-16) induced an increased number of DNA single-strand breaks in NYH/TPT cells. However, sensitivity to different topoisomerase II-targeting agents in NYH/TPT cells varied from increased to decreased, indicating a role for as yet unidentified factors acting on the pathway to cell death after topoisomerase II-induced DNA damage has occurred. Of 20 anti-cancer agents tested, only hydroxyurea showed marked collateral hypersensitivity in NYH/TPT cells.
Sorensen
M
M
Department of Pathology, Sundby Hospital, Copenhagen, Denmark.
Sehested
M
M
Jensen
P B
PB
D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D002250:Carbon Radioisotopes; D018288:Carcinoma, Small Cell / Q000188:drug therapy* / Q000201:enzymology; D004249:DNA Damage; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000032:analysis; D004268:DNA-Binding Proteins; D004351:Drug Resistance; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007527:Isoenzymes / Q000032:analysis; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D059004:Topoisomerase I Inhibitors; D019772:Topotecan; D014407:Tumor Cells, Cultured / Q000187:drug effects*
D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D002250:Carbon Radioisotopes; D004268:DNA-Binding Proteins; D007527:Isoenzymes; D059004:Topoisomerase I Inhibitors; D019772:Topotecan; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II; D002166:Camptothecin