The Study for Non-cross Resistant Alternating Chemotherapy for Bladder Cancer

一种顺式二胺二氯铂（CDDP）耐药细胞系CL-7/CDDP已通过将亲本人类膀胱癌细胞系T24（CL-7）长期暴露于CDDP浓度逐渐增加的环境中20个月而建立。菌落形成试验结果显示，CL-7 /CDDP对CDDP的抗性是CL-7的2.7倍。检测了CL-7/CDDP的生物学和生化特性，并与CL-7进行比较。两种细胞系在倍增时间和镀膜效率上没有差异，但在染色体数目模式上差异较小。CDDP暴露后细胞内CDDP浓度在两种细胞系之间没有差异，但CL-7/CDDP显示出更高的谷胱甘肽（GSH）和金属硫蛋白（MT）水平。提示CDDP获得性耐药机制与细胞内解毒有关，而非外排机制。用集落形成实验检测了CL-7/CDDP对其他抗癌药物的敏感性，并与白血病细胞系CL-7进行了比较。因此，根据耐药程度可将这些药物分为3类；对CDDP具有同等耐药程度的药物（CDDP衍生物、MMC、VP-16）、细胞无耐药的药物（ADM、CTX、IFO、VLB）和杀细胞作用增强的药物（5-FU、MTX）。CDDP衍生物的耐药程度以DWA-2114R最高，其次为CBDCA、NK-121和254-S。还进行了体内研究。为了确定抗癌药物对裸鼠的抗肿瘤作用，分别皮下接种10^7/体的CL-7和CL-7/CDDP细胞，当估计肿瘤重量达到100mg时，腹腔注射抗癌药物。CDDP各剂量2mg/kg、4mg/kg或8mg/kg，每5天给药3次。CDDP 8mg/kg组对CL-7和CL-7/CDDP肿瘤均有抑制作用，但对CL-7/CDDP肿瘤的耐药不明显。对于CL-7/CDDP肿瘤，肿瘤生长缓慢，个体间肿瘤重量分散较大，有待改善。这些结果提示使用这三组药物进行无交叉耐药交替化疗的可能性。少

A cis-diamminedichloroplatinum(CDDP)-resistant cell line, CL-7/CDDP, has been established by chronic exposure of a parent human bladder cancer cell line, T24(CL-7), to CDDP at progressively increaced concentration for twenty months. CL-7 /CDDP was 2.7-fold more resistant to CDDP than CL-7 as determined by colony formation assay. Biological and biochemical characteristics were examined in CL-7/CDDP to compare with CL-7. There were no differences in doubling time and plating efficiency between the two cell lines, but a small one in the mode of chromosome numbers. Intra-cellular CDDP concentration after CDDP exposure showed no difference between the two cell lines, but CL-7/CDDP showed a higher glutathione(GSH)and metallothionein(MT)level. It is suggested that the mechanism of acquired resistance to CDDP is attributed to intra-cellular detoxication, but not to the efflux.The sensitivity of CL-7/CDDP for other anticancer drugs were examined by colony formation assay to compare with the par … More ent cell line, CL-7. Consequently, these drugs could be classified into 3 groups according to the degree of resistance ; drugs with an equal degree of resistance to that of CDDP(CDDP derivatives, MMC, VP-16), drugs for which the cells showed no resistance(ADM, CTX, IFO, VLB), and drugs whose cytocidal effects were enhanced(5-FU, MTX). The degree of resistance in the CDDP derivatives was the highest in DWA-2114R, decreesing in the following order in CBDCA, NK-121, and 254-S.An in vivo study was also performed. To determine the anti-tumor effects of anti-cancer drugs in nude mice, CL-7 and CL-7/CDDP cells of 10^7/body each were inoculated subcutaneouly, and the anti-cancer drug was administered intraperitoneally, when estimated tumor weight reached 100mg. Each dose of 2mg/kg, 4mg/kg, or 8mg/kg of CDDP was administered 3 times every 5 days. The inhibition of tumor growth was observed in the CDDP 8mg/kg group with the CL-7 and CL-7/ CDDP tumor, but the resistance to CDDP in the CL-7/CDDP tumor was not clear. Concerning the CL-7/CDDP tumor, the tumor growth was very slow and the dispertion of tumor weight among individual animals was large, which had to be improved.These results indicated the possibility of non-crosss resistant alternating chemotherapy using these three groups of drugs. Less