| Budget Amount *help |
¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 1993: ¥1,500,000 (Direct Cost: ¥1,500,000)
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| Research Abstract |
Two different types of studies were undertaken by this joint program. For this study, Dr.Takeguchi and Dr.Sakai separately visited the University of Zurich, Institute of Veterinary Physiology, Zurich, Switzerland, and did experimental works. Dr.Diener at University Zurich visited Toyama Medical and Pharmaceutical University, Faculty of Pharmaceutical Sciences, Toyama, Japan, and did experimental works.
1) We used a new rat mutant with chronic conjugated hyperbilirubinemia. Previously, it was reported that the secretary mechanism of organic anion was absent in hepatocytes of the rats by others. We found the function of multi-drug efflux pump in the hepatocytes was also impaired, although its gene-product is correctly expressed. The secretery rate of bile also decreased. The function of the cell volume regulatory mechanism upon hypotonic stress worked, however, its rate was decreased compared with normal rats. These results have shown that the mulfuctions are due to both genetic defect and deterioration of intracellular environments.
2) A new antitumor drug CPT-11 was recently developed in Japan. Its phase II study has shown that this drug is very active against virtually all tumor types including non-small cell lung cancer, to which no active antitumor drug was known previously. This drug's dose-limiting is due to diarrhea and leukopenia. To solve the mechanism of this diarrhea is to increase the dose, which results in increased efficacy. In this joint study, we found that this cholera-like diarrhea was due to the production of thromboxanes by CPT-11 and its metabolite SN-38. The mechanism of diarrhea induced by thromboxane is new and not previously reported in animal models.
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