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

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• 作者：van Hattum ; Annemarie H. ; Pinedo ; Herbert M. ; Schlü ; per ; Hennie M.M. ; Erkelens ; Caroline A.M. ; et. al.
• 关键词：Pgp ; P170-glycoprotein ; MRP1 ; multidrug resistance-associated protein 1 ; LRP ; lung resistance protein ; BCRP ; Breast Cancer Resistance Protein ; MTT ; (3-(4 ; 5-dimethylthiazol-2-yl)-2 ; 6-dimethyl-morpholino)-2 ; 5-diphenyl-tetrazolium bromide ; RF ; resistance fac
• 刊名：Biochemical Pharmacology
• 出版年：2002
• 出版时间：October 15, 2002
• 年：2002
• 卷：64
• 期：8
• 页码：1267-1277
• 全文大小：301 K

文摘

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×5 or weekly×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.