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

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 EC(50) 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 [(3)H]colchicine for binding to tubulin (K(i) = 0.65 micro M); however, it did not compete with [(3)H]paclitaxel or [(3)H]vincristine. There was an accumulation of cells in G(2)-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 ( approximately 350 mm(3)) 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.

• Authors: 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 2nd, David J Frost, Hing L Sham, Saul H Rosenberg, Shi-Chung Ng
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 2 Issue 3 Pg. 227-33 (Mar 2003) ISSN: 1535-7163 [Print] United States
• PMID: 12657717 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Cell Cycle Proteins
• Indoles
• Oxazoles
• Tubulin
• Vincristine
• CASP3 protein, human
• Casp3 protein, mouse
• Caspase 3
• Caspases
• Paclitaxel
• A 289099
• Colchicine

Topics

• Administration, Oral
• Animals
• Antineoplastic Agents (metabolism, therapeutic use)
• Apoptosis (drug effects)
• Binding Sites
• Caspase 3
• Caspases (metabolism)
• Cell Cycle (drug effects)
• Cell Cycle Proteins (metabolism)
• Cell Division (drug effects)
• Colchicine (metabolism)
• Dose-Response Relationship, Drug
• Female
• Humans
• In Situ Nick-End Labeling
• Indoles (metabolism, therapeutic use)
• Mice
• Mice, Inbred C57BL
• Mitosis (drug effects)
• Oxazoles (metabolism, therapeutic use)
• Paclitaxel (pharmacology)
• Sarcoma, Experimental (drug therapy, metabolism, pathology)
• Tubulin (metabolism)
• Tumor Cells, Cultured (drug effects, metabolism)
• Vincristine (pharmacology)