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&F104864 (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‐895lf 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. Int. J. Cancer 72:680–686, 1997. © 1997 Wiley‐Liss, Inc.