Dingemans A C, van Ark-Otte J, Span S, Scagliotti G V, van der Valk P, Postmus P E, Giaccone G
Department of Medical Oncology, University Hospital, Vrije Universiteit, Amsterdam, The Netherlands.
Lung Cancer. 2001 May;32(2):117-28. doi: 10.1016/s0169-5002(00)00224-5.
Resistance to chemotherapy is common in non-small cell lung cancer. The aim of this study was to investigate the prognostic impact of in vitro established drug resistance markers on the response to chemotherapy in patients with advanced non-small cell lung cancer. Samples of 38 patients were analyzed by immunohistochemical staining, for topoisomerase IIalpha and IIbeta, Ki-67, MRP and LRP. In addition, mutation analysis of the topoisomerase IIalpha gene, the B/DNBS and the Tyr804 region, was performed. Lung tumor biopsies were taken prior for treatment with one of the following regimens; cisplatin/paclitaxel, cisplatin/VM26 or VP16, or carboplatin/VP16/ifosfamide. Seventeen patients obtained a partial response, 12 had stable disease and nine patients had progressive disease. None of the investigated markers was related with overall response rate. In one sample a point mutation in the B/DNBS region of the topo IIalpha gene was detected which substitutes IIe(510) with Val. This tumor had a partial response to four courses of cisplatin/VP16 treatment. The survival analysis showed that the patients with high topo IIalpha expressing tumors had a significantly worse survival compared with the patients with low or intermediate topo IIalpha expressing tumors. In conclusion, no relation was observed between expression of topoisomerase IIalpha, IIbeta, Ki-67, MRP or LRP and response rate. Furthermore, worse survival was seen in patients with high topoisomerase IIalpha expressing tumors. In one tumor sample, a newly described mutation in the B/DNBS region of the topo IIalpha gene was detected, which does not appear to be related to drug resistance.
化疗耐药在非小细胞肺癌中很常见。本研究的目的是调查体外建立的耐药标志物对晚期非小细胞肺癌患者化疗反应的预后影响。通过免疫组织化学染色分析了38例患者的样本，检测拓扑异构酶IIα和IIβ、Ki-67、多药耐药相关蛋白（MRP）和肺耐药蛋白（LRP）。此外，还对拓扑异构酶IIα基因的B/DNBS和Tyr804区域进行了突变分析。在采用以下方案之一进行治疗前采集肺肿瘤活检样本：顺铂/紫杉醇、顺铂/威猛（VM26）或依托泊苷（VP16），或卡铂/VP16/异环磷酰胺。17例患者获得部分缓解，12例病情稳定，9例病情进展。所研究的标志物均与总缓解率无关。在一个样本中检测到拓扑异构酶IIα基因B/DNBS区域的一个点突变,该突变使异亮氨酸（Ile）（510）被缬氨酸替代。该肿瘤对四个疗程的顺铂/VP16治疗有部分反应。生存分析表明，与拓扑异构酶IIα低表达或中等表达的肿瘤患者相比，拓扑异构酶IIα高表达肿瘤患者的生存期明显更差。总之，未观察到拓扑异构酶IIα、IIβ、Ki-67、MRP或LRP的表达与缓解率之间存在关联。此外，拓扑异构酶IIα高表达肿瘤患者的生存期更差。在一个肿瘤样本中，检测到拓扑异构酶IIα基因B/DNBS区域一个新描述的突变，该突变似乎与耐药无关。
