Andrews P A, Jones J A, Varki N M, Howell S B
Department of Medicine, University of California, San Diego, La Jolla 92093.
Cancer Commun. 1990;2(2):93-100. doi: 10.3727/095535490820874641.
We have characterized the acquisition of resistance to cisplatin (DDP) in an in vivo solid tumor model. Human ovarian carcinoma cells (2008 cell line) were grown s.c. as xenografts in athymic mice. Tumors were selected with 3.0 mg/kg of DDP i.p. given once per week for four weeks. One week after the last dose of DDP, cell lines were generated from the tumors. Cells from these lines were then re-inoculated into athymic mice, and the DDP selection process was repeated. This procedure was continued for a total of four passages (16 doses). Although this chemotherapy did not affect the tumors' growth, cell lines derived from these tumors after the first passage displayed low-level resistance to DDP as determined by the concentration causing 50% inhibition of colony formation in a clonogenic assay. The mean resistance (+/- SD) of cell lines derived from tumors treated with four doses of DDP was 1.6 +/- 0.06 (n = 5). A minimum of only two doses of DDP was required to generate significant resistance (1.5 fold). The DDP resistance slowly increased with further selections so that after four passages with chemotherapy, the cells were 3.0-fold resistant. The DDP resistance was not stable; after three passages, resistance slowly declined over 104 days from 2.2- to 1.4-fold. Resistant cells obtained after both three and four passages did not have elevated glutathione as determined by flow cytometry of monochlorobimane-stained cells. After three passages, DDP-resistant cells were not resistant to CdCl2, suggesting that metallothioneins were also not elevated. A key biochemical change found in these cells was a decrease in DDP accumulation.(ABSTRACT TRUNCATED AT 250 WORDS)
我们已经在体内实体瘤模型中对顺铂（DDP）耐药性的获得进行了表征。人卵巢癌细胞（2008细胞系）在无胸腺小鼠体内皮下生长成异种移植物。用3.0mg/kg的DDP腹腔注射选择肿瘤，每周一次，共四周。在最后一剂DDP给药一周后，从肿瘤中生成细胞系。然后将这些细胞系的细胞重新接种到无胸腺小鼠体内，并重复DDP选择过程。这个程序总共持续进行了四轮传代（16剂）。尽管这种化疗不影响肿瘤生长，但首次传代后从这些肿瘤衍生的细胞系对DDP显示出低水平耐药，这通过克隆形成试验中导致50%集落形成抑制的浓度来确定。用四剂DDP处理的肿瘤衍生细胞系的平均耐药性（±标准差）为1.6±0.06（n = 5）。产生显著耐药性（1.5倍）仅需要最少两剂DDP。随着进一步选择，DDP耐药性缓慢增加，因此经过四轮化疗传代后，细胞具有3.0倍耐药性。DDP耐药性不稳定；三轮传代后，耐药性在104天内从2.2倍缓慢下降至1.4倍。通过单氯双硫腙染色细胞的流式细胞术测定，三轮和四轮传代后获得的耐药细胞中谷胱甘肽水平均未升高。三轮传代后，DDP耐药细胞对CdCl2不耐药，这表明金属硫蛋白水平也未升高。在这些细胞中发现的一个关键生化变化是DDP积累减少。（摘要截断于250字）
