zinostatin and Disease-Models--Animal

Previous studies from our laboratory have demonstrated that Bcl-2 has a proapoptotic effect on neocarzinostatin (NCS)-treated PC12 pheochromocytoma cells. In the present study, we examine the mechanisms of this effect and demonstrate its relevance for the in vivo situation. Four hours after NCS treatment, a 23-kDa cleavage product of Bcl-2 was detected in whole cell lysates of bcl-2-transfected PC12 cells. In contrast, bcl-2 transfection protected PC12 cells from cisplatin-induced apoptosis, and cisplatin treatment did not result in Bcl-2 cleavage. Similarly, Bcl-2 cleavage did not occur and Bcl-2-mediated protection from, rather than potentiation of apoptosis was observed after NCS treatment of MCF-7 breast cancer cells. The caspase 3-specific inhibitor Ac-DEVD-CHO prevented Bcl-2 cleavage and attenuated NCS-induced apoptosis in bcl-2-transfected PC12 cells, whereas it had no effect on NCS-induced apoptosis in mock-transfected PC12 cells. Furthermore, MCF-7 cells do not express caspase 3, a finding in concert with the lack of Bcl-2 cleavage in this line. In in vivo experiments, xenografts of bcl-2-transfected PC12 cells were more susceptible to NCS toxicity than were xenografts of mock-transfected PC12 cells. Caspase 3-mediated Bcl-2 cleavage therefore plays an important role in the potentiation by Bcl-2 of NCS-induced apoptosis.

Topics: Animals; Antineoplastic Agents; Apoptosis; Caspase 3; Caspase Inhibitors; Caspases; Cisplatin; Cysteine Proteinase Inhibitors; Disease Models, Animal; Drug Interactions; Drug Screening Assays, Antitumor; Humans; Mice; Mice, Nude; Oligopeptides; PC12 Cells; Proto-Oncogene Proteins c-bcl-2; Rats; Transfection; Tumor Cells, Cultured; Xenograft Model Antitumor Assays; Zinostatin

Antitumor activities of zinostatin stimalamer (YM881) were examined in human hepatoma cell lines (SK-Hep1 and HuH2) and VX2 liver tumor-bearing rabbits. YM881 inhibited the growth of human hepatoma cells in a dose-dependent manner. The IC50 values of YM881 causing a 50% inhibition of growth of SK-Hep1 and HuH2 cells were 6.7 and 27 nM, respectively. In VX2 tumor-bearing rabbits, administration of YM881 suspended in Lipiodol, an iodinated fatty acid ethylester of poppyseed oil, (YM881/Lipiodol suspension, 0.2 mg/0.2 ml/body) into the hepatic artery showed significant (p < 0.01, vs. sham-operated and Lipiodol-treated groups) inhibitory effects on tumor growth and histopathological changes at 1 and 2 weeks after administration. In contrast, Lipiodol (0.2 ml/body) tended to inhibit the growth of VX2 tumor (p < 0.1, vs. sham-operated group) at 1 week after administration, but showed only moderate effects at 2 weeks after administration. Minimal necrosis was observed at 1 and 2 weeks after administration of Lipiodol, and histopathological findings were similar to those in the sham-operated group. From the present study, it is suggested that YM881/Lipiodol suspension showed antitumor activity in VX2 tumor-bearing rabbits presumably due to the inhibition of the growth of hepatoma cells by YM881 itself. Lipiodol, on the other hand, is considered to augment the antitumor activity of YM881 by maintaining high YM881 concentrations in tumor tissue.

Topics: Animals; Antineoplastic Agents; Carcinoma, Hepatocellular; Cell Division; Disease Models, Animal; Drug Screening Assays, Antitumor; Humans; Iodized Oil; Liver Neoplasms; Liver Neoplasms, Experimental; Male; Maleic Anhydrides; Neoplasm Transplantation; Polystyrenes; Rabbits; Suspensions; Tumor Cells, Cultured; Zinostatin

Meningeal gliomatosis (MG), pathologically, is caused by the diffuse dissemination or infiltration of glioma cells in the subarachnoid space, for which an effective, systematic treatment has not been contrived. Although, in the case of malignant leptomeningeal tumor, in general, intrathecal chemotherapy with such anticancer drugs as methotrexate and cytosine arabinoside (Ara-C) has been applied, the effect of this kind of treatment is limited, especially on MG. Therefore, the development of a new type of treatment is urgently needed. According to recent reports, neocarzinostatin (NCS) has been disclosed to have a strong cytocidal effect on glioma cells instead of injuring normal glia cells, and the intrathecal injection of NCS is suggested to be effective on MG. In order to evaluate the efficacy of intrathecal treatment with NCS on MG, a rat MG model using C 6 glioma cells has been produced and intrathecal chemotherapy with NCS was performed on this MG model. In MG rats which were treated intrathecally with NCS (1 microgram/kg) 1 day after tumor inoculation, the survival time was significantly prolonged by this treatment, where % ILS was 52.1%. Furthermore, it was more significantly prolonged with 10 micrograms/kg NCS, where 108.5% of % ILS was obtained. Contrary to these effects, this prolongation of the survival time of MG rats by the treatment with NCS showed a tendency to decrease in MG rats treated with NCS 3 days after tumor inoculation. No chemotherapeutic effect was observed in MG rats treated with even 100 micrograms/kg NCS 5 days after tumor inoculation. In conclusion, intrathecal chemotherapy with a low dose of NCS was proved to be effective in the early stages of MG.

Topics: Animals; Antibiotics, Antineoplastic; Disease Models, Animal; Glioma; Male; Meningeal Neoplasms; Neoplasm Transplantation; Rats; Rats, Inbred Strains; Zinostatin