PD806: a novel oral vascular disrupting agent shows antitumor and antivascular effects in vitro and in vivo. Issue 2 (February 2015)

• Record Type: Journal Article
• Authors: Yao, Nan; Gao, Meng; Ren, Ke; Jiang, Xiao; Li, Yue; Jiang, Cuihua; Huang, Dejian; Liu, Wei; Wang, Xiaoning; Fang, Zhijun; Sun, Ziping; Zhang, Jian; Ni, Yicheng
• Is Part Of: Anti-cancer drugs. Volume 26:Issue 2(2015)
• Publication Date: 2015-02
• Subjects: antitumor -- magnetic resonance imaging -- PD806 -- prodrug -- vascular disrupting agent; Antineoplastic agents -- Periodicals; Cancer -- Chemotherapy -- Periodicals; Antineoplastic Agents -- therapeutic use -- Periodicals; Drug Therapy -- Periodicals; 616.994061
• DOI: 10.1097/CAD.0000000000000168
• Languages: English
• ISSNs: 0959-4973

Abstract

Abstract : The aim of this study was to investigate the antitumor and antivascular effects of PD806, a new oral prodrug of AVE8063 in vitro and in vivo . The cytotoxicity of PD806 was determined against H22, Walker 256, A549, MCF-7, and BEL-7402 cells using MTT assays. Plasma pharmacokinetic analysis of AVE8063 generated in rats after a single oral administration of PD806 was carried out using the high-performance liquid chromatography method. H22 tumor-bearing mice models were used to show the antitumor activity. Antivascular responses were monitored by in vivo MRI and immunohistochemistry (CD31) in W256 tumor-bearing rats. A blood test and histopathology were performed to evaluate the toxicity of PD806. PD806 showed cytotoxicity against five types of tumor cell lines with the IC50 values in the micromolar concentration. A pharmacokinetic study indicated that PD806 converted into the active form, AVE8063, which showed a half-life of 5.24±0.70 h in rats. Daily oral administration of PD806 inhibited the growth of subcutaneously implanted H22 tumors in a dose-dependent manner. The tumor volume in the 300 mg/kg PD806 group was obviously smaller than that of the vehicle control group from day 6 onward ( P <0.05), with inhibition rates of 62% on day 30. PD806 in the three-dose group significantly prolonged the survival of the H22 tumor-bearing mice ( P <0.05). At 24 h after PD806 (150 and 200 mg/kg) was administered orally, tumor vascular shutdown was found on CE-T1WI with the presence of extended necrosis and tumor residue at the periphery. The enhancement ratio decreased significantly from 1.00±0.00 at baseline to 0.26±0.08 and 0.17±0.06, respectively ( P <0.01). The necrosis ratio measured from CE-T1WI increased significantly from 34% in average at baseline to 52.96 and 60.30%, respectively ( P <0.05). Immunohistochemical staining of tumor sections showed a marked reduction in CD31 staining vessels, with microvessel density reduced significantly to 8.71±1.76 and 3.33±1.04, respectively, compared with the vehicle control group ( P <0.01). The results of hematology and histopathology showed that PD806 exerted no obvious toxicity during the treatment period. In conclusion, our results indicate that PD806 is an effective and safe vascular disrupting agent.