Drug resistance and its reversal in urogenital carcinoma

1.利用新建立的人膀胱癌顺铂耐药细胞株和睾丸癌细胞株，研究顺铂耐药机制。结论1.研究发现，药物蓄积减少、细胞内谷胱甘肽升高、T-纤溶酶、谷氨酰半胱氨酸合酶、谷胱甘肽S转移酶pi和金属硫蛋白基因的过度表达共同参与了顺铂耐药的获得。有报道称，在430℃的热休克应激下，癌细胞中DNA拓扑异构酶IIpha(Topo IIpha)的mRNA的量会增加。我们利用人膀胱癌细胞株研究了这种现象的机制，发现一个倒置的CCAAT元件在热休克诱导的人topo IIpha基因的转录激活中发挥了重要作用。我们对新合成的二氢吡啶和咪唑类化合物进行了筛选，以确定它们是否能够克服多药耐药(MDR)，并发现了几种有用的药物，它们不仅可以逆转肾癌的获得性MDR，而且可以逆转肾癌固有的MDR，而不会产生明显的毒性。建立顺铂耐药的人睾丸生殖细胞肿瘤细胞系，并将其接种于裸鼠原位(睾丸)，建立合适的淋巴结转移模型。

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.