Dingemans A M, Witlox M A, Stallaert R A, van der Valk P, Postmus P E, Giaccone G
Department of Medical Oncology, University Hospital Vrije Universiteit, Amsterdam, The Netherlands.
Clin Cancer Res. 1999 Aug;5(8):2048-58.
Drug resistance is a major problem in patients with small cell lung cancer; in fact, most die of resistant disease, despite an initial response. Several markers of drug resistance have been described in preclinical models, but the mechanism of drug resistance in lung cancer patients remains unknown. The objective of this study was to evaluate the role of the expression of a number of markers of drug resistance, proliferation, and apoptosis in relation to response to chemotherapy and survival in patients with small cell lung cancer. Tumor samples were derived from 93 previously untreated patients who were randomized in a Phase III study to receive cyclophosphamide, epirubicine, and etoposide or cyclophosphamide, epirubicine and vincristine alternating with carboplatin and etoposide. Paraffin-embedded samples, derived from the primary tumor site prior to chemotherapy, were analyzed by immunohistochemistry for expression of markers implicated in drug resistance [topoisomerase (topo) IIalpha, topo IIbeta, and multidrug resistance-associated protein], apoptosis (p53, p21, and bcl-2), or proliferation (Ki67). Response prediction was analyzed by chi2 test and logistic regression analysis; overall and disease-free survival curves were compared by log-rank test and Cox regression analysis. Shorter survival was observed in patients with extensive disease (P = 0.037) and poorer performance status (P = 0.028) and in patients whose tumors expressed high topo IIalpha levels (P = 0.01) and high Ki67 (P = 0.024). By multivariate analysis, the following factors were found to be predictive for worse survival: high expression levels of topo IIalpha, Ki67, and bcl-2; male sex; and extensive disease. High topo IIbeta expression was found to be predictive for lower overall and complete response rate. No relationship between apoptotic pathway markers or MRP and response to chemotherapy was observed. In conclusion, high expression of topo IIalpha was predictive of worse survival, and high expression of topo IIbeta was predictive of lower response rates. Furthermore, lower survival probability was observed in patients with bcl-2-positive tumors. Immunohistochemical assessment of these markers in diagnostic biopsies may give important prognostic information and may help selecting patients in the worse prognostic categories for new therapeutic strategies.
耐药性是小细胞肺癌患者面临的一个主要问题；事实上，大多数患者死于耐药性疾病，尽管最初有反应。在临床前模型中已经描述了几种耐药标志物，但肺癌患者的耐药机制仍然未知。本研究的目的是评估一些耐药、增殖和凋亡标志物的表达在小细胞肺癌患者化疗反应和生存方面的作用。肿瘤样本来自93例先前未接受过治疗的患者，这些患者在一项III期研究中被随机分组，接受环磷酰胺、表柔比星和依托泊苷，或环磷酰胺、表柔比星和长春新碱交替联合卡铂和依托泊苷。通过免疫组织化学分析化疗前取自原发肿瘤部位的石蜡包埋样本中与耐药性相关的标志物（拓扑异构酶（topo）IIα、topo IIβ和多药耐药相关蛋白）、凋亡（p53、p21和bcl-2）或增殖（Ki67）的表达。通过卡方检验和逻辑回归分析进行反应预测分析；通过对数秩检验和Cox回归分析比较总生存曲线和无病生存曲线。在广泛期疾病患者（P = 0.037）、体能状态较差的患者（P = 0.028）以及肿瘤表达高水平topo IIα（P = 0.01）和高Ki67（P = 0.024）的患者中观察到较短的生存期。通过多变量分析，发现以下因素可预测生存期较差：topo IIα、Ki67和bcl-2的高表达水平；男性；以及广泛期疾病。发现高topo IIβ表达可预测较低的总缓解率和完全缓解率。未观察到凋亡途径标志物或多药耐药相关蛋白与化疗反应之间的关系。总之，topo IIα的高表达预示生存期较差，topo IIβ的高表达预示缓解率较低。此外，在bcl-2阳性肿瘤患者中观察到较低的生存概率。在诊断性活检中对这些标志物进行免疫组织化学评估可能会提供重要的预后信息，并可能有助于为新的治疗策略选择预后较差的患者。
