fosbretabulin and Body-Weight

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.

Topics: Administration, Oral; Angiogenesis Inhibitors; Aniline Compounds; Animals; Antineoplastic Agents; Body Weight; Cell Line, Tumor; Citrates; Half-Life; Humans; Male; Mice, Inbred Strains; Prodrugs; Rats, Sprague-Dawley; Stilbenes; Survival Rate; Xenograft Model Antitumor Assays

The relation between tumor tissue blood flow (tBF) reduction and antitumor effects was investigated. Changes in tBF of normal tissues (liver, kidney cortex, bone marrow and brain cortex) and tumors (Yoshida sarcoma subline, LY80 and Sato lung carcinoma, SLC) due to i.v. administration of AC7700 (1, 3, 10 mg/kg), one of the combretastatin A-4 derivatives, were measured with the hydrogen clearance method. The change in blood flow in tumor microfoci was also observed directly using a rat transparent chamber. Chemotherapy against the solid tumors (LY80, SLC) was performed by administering AC7700 7 times at intervals of 3 days and the effect on the tumor growth, the histological effect, the effect on lymph node metastasis and the survival rate were investigated. Tumor tBF showed a dose-dependent response to AC7700. Although tumor tBF decreased markedly at a dose of 1 mg/kg, it tended to recover partly within several hours. At 10 mg/kg, however, tumor tBF completely stopped within approximately 30 min and never recovered in many regions. The irreversible stoppage of tumor tBF was observed in large s.c. tumors and in microfoci as well. On the other hand, in normal tissues, tBF changes due to AC7700 were not uniform. In the liver, although tBF decreased by approximately 50% at 10 mg/kg AC7700, it recovered within 8 h. In the brain, although the mean maximum reduction was 35%, the blood flow recovered to the original level within 24 h. The blood flow in the kidney cortex did not change at all. In the bone marrow, tBF decreased by approximately 80%. Generally, the blood flow reduction in normal tissues tended to be reversible. The effect on tumor growth and the histological effect were also dependent on the dose of AC7700. The tumor growth was markedly inhibited by 10 mg/ kg AC7700 and extensive necrosis was induced. Lymph node metastases were significantly inhibited and survival was prolonged significantly. In the control group, all 8 SLC tumor-bearing rats died of cancer, the presence of which was verified by gross and microscopic evaluation, within 45 days after tumor implantation. On the other hand, in the treated group, 2 of 8 rats recovered completely and survived. No obvious side effects such as body weight loss, anemia or diarrhea were observed at the dose used in this experiment. From these results, we conclude that strong antitumor effects are obtained by stopping tumor tBF irreversibly and by shutting off the nutritional supply into tumor tissue. AC7700

Topics: Animals; Antineoplastic Agents; Blood Pressure; Body Weight; Disease Models, Animal; Drug Screening Assays, Antitumor; Lymphatic Metastasis; Male; Neoplasm Transplantation; Neoplasms, Experimental; Rats; Regional Blood Flow; Serine; Stilbenes; Survival Rate