Oshita F, Yamamoto N, Fukuda M, Ohe Y, Tamura T, Eguchi K, Shinkai T, Saijo N
Department of Medical Oncology, National Cancer Center Hospital, Tokyo, Japan.
Cancer Res. 1995 Jun 1;55(11):2334-7.
A pilot study was conducted in patients with advanced non-small cell lung cancer to examine whether the gene-specific damage in mononuclear cells (MNCs) incubated with cisplatin in vitro correlates with chemotherapeutic outcome in cisplatin-based chemotherapy. Twenty-one patients received cisplatin-based chemotherapy, consisting of cisplatin (80 mg/m2 i.v. on day 1), vindesine (3 mg/m2 i.v. on days 1 and 8), with or without mitomycin (8 mg/m2 i.v. on day 1). MNCs from peripheral blood were obtained from each patient before chemotherapy. The cells were incubated with cisplatin for 3 h in vitro and the 2.7-kb fragment of the hypoxanthine phosphoribosyltransferase gene was amplified by PCR for quantitation of DNA damage. There was a 4-fold interpatient variation in DNA damage in MNCs. Seven of 21 patients had a partial response to chemotherapy. When the dose of cisplatin required to reduce amplification of the hypoxanthine phosphoribosyltransferase sequence by 63% (D63 value) of MNCs was compared in each patient (defined by a Poisson distribution as the dose that produced an average of one lesion per single strand of the 2.7-kb fragment), the mean D63 value in patients showing a partial response (n = 7; 52 +/- 11 micrograms/ml) was significantly lower than that in patients showing no change (n = 10; 81 +/- 20 micrograms/ml; P = 0.0045) and in patients with disease progression (n = 4; 115 +/- 34 micrograms/ml; P = 0.0012). The mean D63 in patients with no change was also significantly lower than that in the patients with disease progression (P = 0.0386). Seven (70%) of 10 patients with a D63 value < 70 micrograms/ml were responders. No relationship was observed between the D63 values and hematological and nonhematological toxicities. It is suggested that DNA damage in MNCs incubated by cisplatin treatment in vitro in responders was greater than that in nonresponders. Gene-specific damage in MNCs from peripheral blood incubated with cisplatin in vitro assayed by PCR may predict the chemotherapeutic response in cisplatin-based chemotherapy for non-small cell lung cancer.
进行了一项针对晚期非小细胞肺癌患者的初步研究，以检验体外与顺铂孵育的单核细胞（MNC）中的基因特异性损伤是否与基于顺铂的化疗的治疗结果相关。21例患者接受了基于顺铂的化疗，包括顺铂（第1天静脉注射80mg/m²）、长春地辛（第1天和第8天静脉注射3mg/m²），有或无丝裂霉素（第1天静脉注射8mg/m²）。化疗前从每位患者获取外周血中的MNC。将细胞与顺铂在体外孵育3小时，通过PCR扩增次黄嘌呤磷酸核糖基转移酶基因的2.7kb片段以定量DNA损伤。MNC中的DNA损伤在患者间存在4倍的差异。21例患者中有7例对化疗有部分反应。当比较每位患者使MNC中次黄嘌呤磷酸核糖基转移酶序列扩增减少63%（D63值）所需的顺铂剂量时（根据泊松分布定义为在2.7kb片段的单链上平均产生一个损伤的剂量），有部分反应的患者（n = 7；52±11μg/ml）的平均D63值显著低于无变化的患者（n = 10；81±20μg/ml；P = 0.0045）和疾病进展的患者（n = 4；115±34μg/ml；P = 0.0012）。无变化的患者的平均D63值也显著低于疾病进展的患者（P = 0.0386）。D63值<70μg/ml的10例患者中有7例（70%）为反应者。未观察到D63值与血液学和非血液学毒性之间的关系。提示在体外经顺铂处理孵育的MNC中，反应者的DNA损伤大于无反应者。通过PCR检测体外与顺铂孵育的外周血MNC中的基因特异性损伤，可能预测非小细胞肺癌基于顺铂化疗的治疗反应。
