DX-8951f, a water-soluble camptothecin analog, exhibits potent antitumor activity against a human lung cancer cell line and its SN-38-resistant variant.
We previously reported that DX-8951f, a novel water-soluble camptothecin analog, significantly inhibits the growth of various human and murine tumors in vitro and in vivo. The antitumor effects and topoisomerase I inhibitory activity of DX-8951f are stronger than those of other current camptothecin analogs. In this study, we established an SN-38-resistant cell line, PC-6/SN2-5, from the human oat cell carcinoma PC-6 cell line by a stepwise selection system, investigated the mechanism of resistance of this cell line and then compared the antitumor activity of camptothecin analogs against the cell line. PC-6/SN2-5 cells were resistant to SN-38 (32-fold) and SK&F 104864 (topotecan; 14-fold), but barely resistant to CPT-11 (3-fold) and DX-8951f (2-fold). Topoisomerase I protein levels and topoisomerase I activities of parental cells were similar to those of resistant cells. Determination of the cellular drug concentration by either flow cytometric analysis or the high-performance liquid chromatography method confirmed that the cellular accumulation of SN-38 and topotecan was significantly reduced in PC-6/SN2-5 cells, whereas that of DX-8951f was only slightly reduced. Furthermore, DX-8951f stabilized the cleavable complex formations in intact PC-6/SN2-5 cells as well as in parental cells, but SN-38 and topotecan did not in the resistant cells. Our data suggest that PC-6/SN2-5 cells may have acquired resistance to camptothecin analogs by a decrease in intracellular drug accumulation and that DX-8951f may have the potency to overcome such a type of resistance mechanism induced by camptothecin compounds.
Joto
N
N
New Product Research Laboratories IV, Daiichi Pharmaceutical Company Ltd., Tokyo, Japan.
Ishii
M
M
Minami
M
M
Kuga
H
H
Mitsui
I
I
Tohgo
A
A
D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics / Q000494:pharmacology*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D018288:Carcinoma, Small Cell / Q000188:drug therapy* / Q000378:metabolism; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004273:DNA, Neoplasm / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D004355:Drug Stability; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology; D005434:Flow Cytometry; D006801:Humans; D000077146:Irinotecan; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D012995:Solubility; D059004:Topoisomerase I Inhibitors; D019772:Topotecan; D014407:Tumor Cells, Cultured; D014867:Water
D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D004273:DNA, Neoplasm; D004791:Enzyme Inhibitors; D059004:Topoisomerase I Inhibitors; D014867:Water; D000077146:Irinotecan; D019772:Topotecan; D004264:DNA Topoisomerases, Type I; C095887:exatecan; D002166:Camptothecin