The activity profile of the hexacyclic camptothecin derivative DX-8951f in experimental human colon cancer and ovarian cancer.

DX-8951f or exatecan mesylate ((1S,9S)-1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-10-13(9H,15H)-dione methanesulfonate dihydrate), is a new water-soluble derivative of camptothecin. We determined the activity of DX-8951f in experimental human colon cancer and ovarian cancer, being tumor types sensitive to camptothecins. With the use of the MTT assay, DX-8951f was more potent than SN-38 in four out of five human colon cancer cell lines and three out of four human ovarian cancer cell lines (P<0.05). DX-8951f was considerably more potent than topotecan in all cell lines tested (P<0.05). Prolonged exposure to DX-8951f resulted in a greater increase in inhibition of cell proliferation as compared to that obtained with SN-38 or topotecan (P<0.05). Overexpression of Pgp, MRP1, and LRP did not affect the in vitro activity of DX-8951f. DX-8951f administered daily x 5 or weekly x 2 resulted in growth inhibition <50% in two human colon cancer xenografts grown s.c. in nude mice. In three human ovarian cancer xenografts, however, >50% growth inhibition was observed at both schedules. In the OVCAR-3 human ovarian cancer model, DX-8951f showed considerably greater activity than topotecan (P<0.01). DX-8951f combined with cisplatin or paclitaxel did not indicate the presence of a pharmacological interaction. In OVCAR-3 xenografts the combination was clearly more effective than DX-8951f alone, as the number of complete remissions increased substantially. In conclusion, this study shows that DX-8951f is highly potent in vitro and highly effective in experimental human ovarian cancer in vivo. Prolonged exposure to DX-8951f in vitro greatly increased the antiproliferative effects, which may be a rationale for testing a continuous infusion schedule in the clinic. Addition of cisplatin or paclitaxel improved the in vivo antitumor effects of DX-8951f.

Novel camptothecin derivative BNP1350 in experimental human ovarian cancer: determination of efficacy and possible mechanisms of resistance.

The novel camptothecin derivative BNP1350 (7-[2-trimethylsilyl)ethyl]-20(S)-camptothecin), also known as Karenitecin, has been developed for superior oral bioavailability and increased lactone stability. In our study, we describe the antiproliferative effects of BNP1350, SN-38 and topotecan in 4 human ovarian cancer cell lines. BNP1350 was found to be slightly more potent than SN-38 (p<0.01) and was considerably more potent than topotecan (p<0.01). We extended these studies to well-established human ovarian cancer xenografts in which we compared the growth inhibition induced by BNP1350 with that of topotecan given in equitoxic schedules. The growth inhibition in all 3 xenografts induced by BNP1350 was > or =75%, which was significantly better than that resulting from topotecan (p<0.05). We then selected BNP1350-resistant variants of the A2780 human ovarian cancer cell line, 2780K4 (resistance factor: 41) and 2780K32 (resistance factor: 90), to analyze possible resistance mechanisms. These variants exhibited cross-resistance against all camptothecins tested. In comparison with 2780K4 cells, 2780K32 cells were relatively more resistant against SN-38, topotecan, DX-8951f and BNP1350. In addition, 2780K32 cells were highly cross-resistant against mitoxantrone. In both 2780K4 and 2780K32, the amount of topoisomerase I was not changed but the catalytic activity was reduced. Furthermore, 2780K32 cells clearly overexpressed the breast cancer resistance protein (BCRP), as demonstrated for both the gene and the protein. In contrast to topotecan, BNP1350 proved not to be a good substrate for BCRP. Overall, we conclude that BNP1350 offers advantages over topotecan expressed by high efficacy in experimental human ovarian cancer and poor affinity for BCRP.