Biological activity of A-289099: An orally active tubulin-binding indolyloxazoline derivative

Stephen K. Tahir*, Michael A. Nukkala, Nicolette A. Zielinski Mozny, R. Bruce Credo, Robert B. Warner, Qun Li, Keith W. Woods, Akiyo Claiborne, Stephen L. Gwaltney, David J. Frost, Hing L. Sham, Saul H. Rosenberg, Shi Chung Ng

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

Abstract

In this report, we describe the antitumor activity of A-289099, an indolyloxazoline derivative with antimitotic activity. A-289099 decreased the proliferation of a variety of cells with EC50 values ranging from 5.1 to 12.8 nM in a P-glycoprotein-independent manner. In cultured cells, microtubules depolymerized in a time- and dose-dependent manner when treated with A-289099. In competition-binding assays, A-298099 competed with [ 3H]colchicine for binding to tubulin (Ki = 0.65 μM); however, it did not compete with [3H]paclitaxel or [ 3H]vincristine. There was an accumulation of cells in G2-M after treatment with A-289099 for 8 h and a subsequent increase in a subdiploid population and an increase in caspase-3 activity, indicative of apoptosis after treatment for 24 and 48 h. The antitumor activities of A-289099 were evaluated using the syngeneic M5076 murine reticulum sarcoma flank tumor model. Animals size-matched for established tumors (∼350 mm3) were dosed p.o. (50 mg/kg every day) for 11 days starting on day 10 postinoculation. Tumors from A-289099-treated animals regressed throughout the 11-day dosing period with a percentage of the average treated-tumor-volume divided by the average vehicle-control-tumor-volume (% T/C) value of 11% after treatment for 7 days. Examination of tumor sections revealed an increase in internucleosomal DNA fragmentation or cell death within the central core after drug-treatment. A decrease in the perfusion of tumors was observed after drug-treatment that was localized primarily to the central core and closely associated with the regions of cell death. In summary, our findings indicate A-289099 is a promising, orally active tubulin-binding compound with antitumor activity in vivo.

Original languageEnglish (US)
Pages (from-to)227-233
Number of pages7
JournalMolecular cancer therapeutics
Volume2
Issue number3
StatePublished - Mar 1 2003

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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