Siu L L, Banerjee D, Khurana R J, Pan X, Pflueger R, Tannock I F, Moore M J
Department of Medicine, Princess Margaret Hospital, Toronto, Ontario, Canada.
Clin Cancer Res. 1998 Mar;4(3):559-65.
Tissue from primary tumors was analyzed for 118 patients with urothelial cancer who subsequently received cisplatin-based chemotherapy. Immunohistochemical staining was performed for nuclear p53 reactivity; for two proposed mediators of drug resistance, metallothionein (MT) and P-glycoprotein; and for the cell proliferation marker MIB-1. For each marker, immunoreactivity was expressed as a percentage of positively staining cells, and overall intensity of staining was graded on a scale from 0 to 3. The product of these two measurements was calculated to generate a percentage-intensity index. Clinical data were obtained independently via retrospective chart review. Chemotherapy regimens containing cisplatin (cisplatin, methotrexate, and vinblastine or methotrexate, vinblastine, doxorubicin, and cisplatin) were administered for metastatic disease (n = 64), for locally advanced disease (n = 45), or as an adjuvant treatment (n = 9). The overall response rate was 56% among 99 evaluable patients, and median survival was 12.7 months. By univariate analysis, Eastern Cooperative Oncology Group performance status (P = 0.0025), tumor grade (P = 0.03), percentage of MT staining (P = 0.01), and percentage-intensity index of MT staining (P = 0.04) were significant predictors of response to chemotherapy. The first three of these were significant in a multivariate model (P = 0.05, 0.04, and 0.04, respectively). By subgroup analysis, the percentage of MT staining predicted for response in metastatic disease (P = 0.03), but not in locally advanced disease (P = 0.28). Only performance status was significantly related to overall survival (P = 0.0001, log-rank test) in the whole cohort. Overexpression of MT in the 64 patients with metastatic disease was associated with a shorter survival (P = 0.04). Expression of p53, P-glycoprotein, and MIB-1 did not predict for survival. In conclusion, overexpression of MT is associated with a poorer outcome from chemotherapy, possibly due to cisplatin resistance.
对118例随后接受以顺铂为基础化疗的尿路上皮癌患者的原发肿瘤组织进行了分析。进行了核p53反应性的免疫组织化学染色；检测了两种假定的耐药介质金属硫蛋白（MT）和P-糖蛋白；以及细胞增殖标志物MIB-1。对于每种标志物，免疫反应性以阳性染色细胞的百分比表示，染色的总体强度按0至3级进行分级。计算这两个测量值的乘积以生成百分比强度指数。通过回顾性病历审查独立获得临床数据。含顺铂的化疗方案（顺铂、甲氨蝶呤和长春碱或甲氨蝶呤、长春碱、阿霉素和顺铂）用于转移性疾病（n = 64）、局部晚期疾病（n = 45）或作为辅助治疗（n = 9）。99例可评估患者的总缓解率为56%，中位生存期为12.7个月。单因素分析显示，东部肿瘤协作组体能状态（P = 0.0025）、肿瘤分级（P = 0.03）、MT染色百分比（P = 0.01）和MT染色百分比强度指数（P = 0.04）是化疗反应的显著预测因素。其中前三项在多变量模型中具有显著性（分别为P = 0.05、0.04和0.04）。亚组分析显示，MT染色百分比可预测转移性疾病的反应（P = 0.03），但不能预测局部晚期疾病的反应（P = 0.28）。在整个队列中，只有体能状态与总生存期显著相关（P = 0.0001，对数秩检验）。64例转移性疾病患者中MT的过表达与较短的生存期相关（P = 0.04）。p53、P-糖蛋白和MIB-1的表达不能预测生存期。总之，MT的过表达与化疗效果较差相关，可能是由于顺铂耐药。
