TRO 19622

"目录号: HY-14797

Ombrabulin 是 CA-4 磷酸酯的衍生物，选择性破坏内皮细胞的微管蛋白细胞骨架，具有抗血管作用。

生物活性

Description

Ombrabulin is a derivative of CA-4 phosphate, which is known to exhibit antivascular effects through selective disruption of thetubulincytoskeleton of endothelial cells.

IC50& Target

tubulin[1]

In Vitro

The effect of Ombrabulin (AVE8062) on endothelial or tumor cell viability is examined using the MTT assay. The IC50of Ombrabulin for the mouse mesenteric endothelial cells (MMEC) is 10 nM and ranges between 7 and 20 nM for the tumor cell lines (HeyA8, SKOV3ip1, and HeyA8-MDR). Comparative analysis of the nonlinear least-squares regression of the dose-response curves for each agent alone and combination Ombrabulin /Docetaxel show a significantly lower IC50than either agent alone (P<0.005, all cell lines). The cytotoxicity of Docetaxel is 2- to 4-fold greater in combination with Ombrabulin for the endothelial and tumor cells compared with Docetaxel alone[1].

In Vivo

Before performing therapy experiments, the tolerability of various doses of Ombrabulin (AVE8062) ranging from 10 to 100 mg/kg is tested given twice weekly via i.v., i.p., or s.c. routes in nude mice (n=3 per group). The i.v. and s.c. routes are not pursued further due to problems with skin or tail vein necrosis. The i.p. route is well tolerated with doses up to 100 mg/kg. Next, preliminary experiments are done to determine the lowest dose for in vivo therapeutic efficacy. Starting 7 days after tumor cell injection, nude mice (n=5 per group) bearing HeyA8 ovarian cancer cells are treated with either vehicle or Ombrabulin 10, 30, 50, and 100 mg/kg twice weekly i.p. for 3 weeks. There is 65% reduction in tumor weight in the 30 mg/kg group compared with the vehicle control group (P<0.02). The 10 mg/kg dose is not effective. The antitumor effects at doses >30 mg/kg are not significantly better; therefore, the 30 mg/kg dose is selected for subsequent therapy experiments[1].

Clinical Trial

NCT01907685

Sanofi

Advanced Neoplastic Disease

June 2006

Phase 1

NCT01063946

Sanofi

Neoplasms, Malignant

January 2010

Phase 1

NCT00968916