Sanderson B J, Johnson K J, Henner W D
Biotechnology, School of Medicine, Flinders University of South Australia, GPO Box 2100, Adelaide 5001, Australia.
Mutagenesis. 2001 May;16(3):197-202. doi: 10.1093/mutage/16.3.197.
Monitoring patients treated with single antineoplastic agents is aiding our understanding of what hazard these drugs pose in vivo. In this study, the frequency of mutant 6-thioguanine-resistant (TG(R)) peripheral blood lymphocytes was monitored before treatment and for < or =35 weeks after treatment of patients with cyclophosphamide (CP) or chlorambucil (CAB). The mean mutant frequency before treatment for six multiple sclerosis patients treated with high-dose CP was 2.53 x 10(-5) and increased after treatment to 4.61 x 10(-5) (P = 0.08, paired t-test). Using each patient as their own control, there were significant increases (each at P < 0.04) detectable within 2-4 weeks in four of the multiple sclerosis patients treated with CP. There was no increase in an untreated control monitored over the same period. In a patient receiving five sequential CP treatments at 1 month intervals, there were cumulative increases in the frequency of mutant cells. The mutant frequency increased from 0.31 x 10(-5) before treatment to 3.64 x 10(-5) after the final treatment and had decreased to 0.53 x 10(-5) at 35 weeks after treatment. In one of two CAB-treated patients with indolent non-Hodgkin's lymphoma, there was a significant increase in mutant frequency (P < 0.03) after treatment. Freshly isolated peripheral blood lymphocytes treated with 4-hydroperoxy-CP in vitro demonstrate a dose-dependent increase in mutant frequency. The increment in mutant frequency observed in vivo is of the order expected from the in vitro experiments. Although this study demonstrates that single or multiple doses of a single antineoplastic agent are mutagenic in vivo for some patients, further studies are needed to determine the extent and mechanism of the inter-individual variations in mutagenic response.
监测接受单一抗肿瘤药物治疗的患者，有助于我们了解这些药物在体内会造成何种危害。在本研究中，对接受环磷酰胺（CP）或苯丁酸氮芥（CAB）治疗的患者，在治疗前及治疗后≤35周监测其6-硫鸟嘌呤耐药（TG(R)）外周血淋巴细胞的频率。6例接受大剂量CP治疗的多发性硬化症患者治疗前的平均突变频率为2.53×10⁻⁵，治疗后增至4.61×10⁻⁵（配对t检验，P = 0.08）。以每位患者自身作为对照，4例接受CP治疗的多发性硬化症患者在2 - 4周内可检测到显著增加（均为P < 0.04）。同期监测的未治疗对照无增加。在一名每隔1个月接受5次序贯CP治疗的患者中，突变细胞频率有累积增加。突变频率从治疗前的0.31×10⁻⁵增至最后一次治疗后的3.64×10⁻⁵，治疗后35周降至0.53×10⁻⁵。在2例接受CAB治疗的惰性非霍奇金淋巴瘤患者中，有1例治疗后突变频率显著增加（P < 0.03）。体外经4-氢过氧化环磷酰胺处理的新鲜分离外周血淋巴细胞显示突变频率呈剂量依赖性增加。体内观察到的突变频率增加幅度与体外实验预期一致。虽然本研究表明单剂量或多剂量单一抗肿瘤药物对部分患者在体内具有致突变性，但仍需进一步研究以确定个体间致突变反应差异的程度和机制。
