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

Annemarie H. Van Hattum, Herbert M. Pinedo, Hennie M M Schlüper, Caroline A M Erkelens, Akiko Tohgo, Epie Boven

Research output: Contribution to journalArticlepeer-review

27 Scopus citations


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% 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.

Original languageEnglish (US)
Pages (from-to)1267-1277
Number of pages11
JournalBiochemical Pharmacology
Issue number8
StatePublished - Oct 15 2002
Externally publishedYes


  • Colon cancer
  • DX-8951f
  • Human tumor xenografts
  • Ovarian cancer
  • Topoisomerase I inhibitor

ASJC Scopus subject areas

  • Pharmacology


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