McDiarmid M A, Kolodner K, Humphrey F, Putman D, Jacobson-Kram D
Johns Hopkins University, School of Hygiene and Public Health, Baltimore, MD 21205.
Mutat Res. 1992 Jun 1;279(3):199-204. doi: 10.1016/0165-1218(92)90067-a.
Determinations of baseline and mutagen-induced sister-chromatid exchanges (SCE) have been used as indicators of previous mutagen exposure in several human populations. Mutagen-induced SCE is based on the premise that a genetic outcome may depend not only on a present exposure, but also on a cell's "memory" of previous exposure. The genotoxicity of some anti-cancer drugs including cyclophosphamide (CP) has been studied by determining baseline and mutagen-induced SCE in peripheral blood lymphocytes in treated cancer patients. This study examined the in vivo genotoxic effects of occupational exposure to anti-cancer drug handling by relating baseline and phosphoramide mustard (PM) -induced SCE levels with duration of anti-cancer drug handling as a surrogate for anti-cancer drug exposure dose. The mean baseline SCE for the population was 5.19 +/- 0.17 and was not correlated with duration of drug handling. However, a strong correlation was demonstrated between inducible SCE values and life-time duration of drug handling with r = 0.63 (p less than 0.0001 for low-dose PM challenge (0.1 mg/ml PM) and r = 0.67 (p less than 0.0001) for high-dose PM challenge (0.25 mg/ml PM). A similar relationship was seen for PM-induced SCE and duration of anti-cancer drug handling for the workers' present job with correlations obtained being r = 0.63 (p less than 0.0001) for low-dose PM and r = 0.59 (p less than 0.0001) for high dose PM. The short-lived nature of the baseline SCE lesion is discussed as a limitation in population surveillance studies, as it reflects primarily recent mutagen exposure and persists only for days to weeks after exposure. The induced SCE measure is postulated to provide an integrating dosimeter of remote previous exposure, improving upon the current limitation of the baseline SCE measure and allowing the "unmasking" of previous exposure in a provocative framework.
在多个人类群体中，基线及诱变剂诱导的姐妹染色单体交换（SCE）测定已被用作既往诱变剂暴露的指标。诱变剂诱导的SCE基于这样一个前提，即遗传结果可能不仅取决于当前的暴露，还取决于细胞对既往暴露的“记忆”。通过测定接受治疗的癌症患者外周血淋巴细胞中的基线及诱变剂诱导的SCE，已对包括环磷酰胺（CP）在内的一些抗癌药物的遗传毒性进行了研究。本研究通过将基线及磷酰胺氮芥（PM）诱导的SCE水平与抗癌药物处理时长相关联，以抗癌药物处理时长作为抗癌药物暴露剂量的替代指标，来检测职业接触抗癌药物处理的体内遗传毒性效应。该人群的平均基线SCE为5.19±0.17，且与药物处理时长无关。然而，诱导性SCE值与药物处理的终生时长之间呈现出强相关性，低剂量PM激发（0.1 mg/ml PM）时r = 0.63（p＜0.0001），高剂量PM激发（0.25 mg/ml PM）时r = 0.67（p＜0.0001）。对于工人当前工作中PM诱导的SCE与抗癌药物处理时长，也观察到了类似关系，低剂量PM时相关性为r = 0.63（p＜0.0001），高剂量PM时相关性为r = 0.59（p＜0.0001）。基线SCE损伤的短暂性被视为人群监测研究中的一个局限，因为它主要反映近期的诱变剂暴露，且暴露后仅持续数天至数周。据推测，诱导性SCE测量可提供一个既往远程暴露的综合剂量计，克服了当前基线SCE测量的局限性，并能在一个激发性框架中“揭示”既往暴露情况。
