Mechanisms of cisplatin resistance and its reversal in urogential carcinoma

1.建立顺铂耐药的膀胱癌细胞株，探讨顺铂获得性耐药的机制。结论：1.药物蓄积减少、细胞内谷胱甘肽增多、谷胱甘肽S转移酶π和γ谷氨酰半胱氨酸合成酶基因表达增加等多种机制参与了顺铂耐药的获得。探讨人膀胱癌细胞株对顺铂的内源性耐药机制。结果表明，细胞内铂的蓄积与细胞内的内阻有关。我们进行了前瞻性随机研究，以观察P-糖蛋白介导的多药耐药的化疗增敏剂维拉帕米能否增强阿霉素对浅表性膀胱癌经尿道电切术后膀胱内复发的预防作用。我们发现在预防复发方面，维拉帕米和阿霉素联合膀胱内灌注较单用阿霉素有更大的益处。我们对新合成的二氢吡啶和咪唑并噻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，并找到了几个有用的试剂。我们从人睾丸生殖细胞肿瘤细胞系中建立了顺铂耐药生殖细胞肿瘤细胞系，并将其注射到结节小鼠的原位(睾丸)内，建立了一种实用的淋巴转移模型。

1. The mechanisms of acquired resistance to cisplatin was examined using newly established cisplatin resistant bladder cancer cell lines. Multiple mechanisms, including decreased drug accumulation, increased intracellular glutathione and increased expression of glutathione S-transferase π and γ-glutamylcysteine synthetase genes, contributed to the acquisition of cisplatin resistance.2. The mechanisms of intrinsic resistance to cisplatin in human bladder cancer cell lines was investigated. It was revealed that accumulation of intracellular platinum was correlated with intrinsic resistance.3. We performed the prospective randomized study to examined whether verapamil, a chemosensitizing agent of P-glycoprotein-mediated multidrug resistance, could enhance the prophylactic effect of doxorubicin on intravesical recurrence after transurethral resection of superficial bladder cancer. We found that intravesical instillation of verapamil and doxorubicin had a significantly greater beneficial effect than that of doxorubicin alone for preventing recurrence.4. We screened newly synthesized dihydropyridine and imidazothiazole derivatives to determine whether they might be able to overcome multidrug resistance, and found several useful agents.5. We established a cisplatin resistant germ cell tumor cell line from human testicular germ cell tumor cell line and also established an useful model of lymphnode metastasis by injecting the cells into orthotopic site (testis) of node mice.