Drug resistance and its reversal in urogenital carcinoma

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1. The mechanisms of cisplatin resistance was examined using newly established cisplatin resistant human baladder cancer and testicular cancer cell lines. Multiplemechansisms, including decreased drug accumulation, increased intracellular glutathione, overexpression of T-plastin, gamma-glutamylcysteinesynthetase, glutathione S-transferase pi and metallothionein genes were found to participate cooperatively in the acquisition of cisplatin resistance in human cancer.2. It has been reported that the amount of DNA topoisomerase IIalpha (topo IIalpha) mRNA in cancer cells is increased by exposing them to heat shock stress at 430. We investigated the mechanisms of such phenomena using human bladder cancer cell line, and found that an inverted CCAAT element play an important role in transcriptional activation of the human topo IIalpha geneby heat shock.3. We have screened newly synthesized dihydropyridine and imidazothiazole derivatives to determine whether they may be able to overcome multidrug resistance (MDR), and found several useful agents which reverse not only acquired MDR but also intrinsic MDR of kidney cancer without inducing significant toxicity.4. Cisplatin resistant human testicular germ cell tumor cell line was established, and appropriate model of lymph node metastasis was established by injecting the cells into orthotopic site (testis) of the nude mice.