title: PD806: a novel oral vascular disrupting agent shows antitumor and antivascular effects in vitro and in vivo.
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.
authors.affiliation: aLaboratory of Translational Medicine, Jiangsu Province Academy of Traditional Chinese Medicine bDepartment of Nuclear Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing cDepartment of Orthopedics, The Third Affiliated Hospital of Soochow University (The First People's Hospital of Changzhou), Changzhou, Jiangsu Province dShandong Academy of Medical Sciences, Jinan, Shandong, People's Republic of China eDepartment of Radiology, Faculty of Medicine, KU Leuven, Herestraat, Leuven, Belgiume.
authors.forename: Nan
authors.initials: N
authors.lastname: Yao
authors.forename: Meng
authors.initials: M
authors.lastname: Gao
authors.forename: Ke
authors.initials: K
authors.lastname: Ren
authors.forename: Xiao
authors.initials: X
authors.lastname: Jiang
authors.forename: Yue
authors.initials: Y
authors.lastname: Li
authors.forename: Cuihua
authors.initials: C
authors.lastname: Jiang
authors.forename: Dejian
authors.initials: D
authors.lastname: Huang
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Xiaoning
authors.initials: X
authors.lastname: Wang
authors.forename: Zhijun
authors.initials: Z
authors.lastname: Fang
authors.forename: Ziping
authors.initials: Z
authors.lastname: Sun
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.forename: Yicheng
authors.initials: Y
authors.lastname: Ni
mesh_terms: D000284:Administration, Oral; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001835:Body Weight / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects; D002951:Citrates / Q000494:pharmacology*; D006207:Half-Life; D006801:Humans; D008297:Male; D008815:Mice, Inbred Strains; D011355:Prodrugs / Q000008:administration & dosage / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D013267:Stilbenes / Q000494:pharmacology*; D015996:Survival Rate; D023041:Xenograft Model Antitumor Assays
chemical_list: C000600729:AVE-8063; D020533:Angiogenesis Inhibitors; D000814:Aniline Compounds; D000970:Antineoplastic Agents; D002951:Citrates; C000600730:PD806 compound; D011355:Prodrugs; D013267:Stilbenes; C058728:fosbretabulin