title: 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.affiliation: Cancer Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, Illinois 60064, USA. stephen.k.tahir@abbott.com
authors.forename: Stephen K
authors.initials: SK
authors.lastname: Tahir
authors.forename: Michael A
authors.initials: MA
authors.lastname: Nukkala
authors.forename: Nicolette A
authors.initials: NA
authors.lastname: Zielinski Mozny
authors.forename: R Bruce
authors.initials: RB
authors.lastname: Credo
authors.forename: Robert B
authors.initials: RB
authors.lastname: Warner
authors.forename: Qun
authors.initials: Q
authors.lastname: Li
authors.forename: Keith W
authors.initials: KW
authors.lastname: Woods
authors.forename: Akiyo
authors.initials: A
authors.lastname: Claiborne
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Gwaltney
authors.forename: David J
authors.initials: DJ
authors.lastname: Frost
authors.forename: Hing L
authors.initials: HL
authors.lastname: Sham
authors.forename: Saul H
authors.initials: SH
authors.lastname: Rosenberg
authors.forename: Shi-Chung
authors.initials: SC
authors.lastname: Ng
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D003078:Colchicine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D020287:In Situ Nick-End Labeling; D007211:Indoles / Q000378:metabolism / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D008938:Mitosis / Q000187:drug effects; D010080:Oxazoles / Q000378:metabolism / Q000627:therapeutic use*; D017239:Paclitaxel / Q000494:pharmacology; D012513:Sarcoma, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D014404:Tubulin / Q000378:metabolism*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D014750:Vincristine / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D007211:Indoles; D010080:Oxazoles; D014404:Tubulin; D014750:Vincristine; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D017239:Paclitaxel; C456410:A 289099; D003078:Colchicine