Takeshita T, Conner M K
Cancer Res. 1984 Sep;44(9):3820-4.
Sister chromatid exchange (SCE) responses were evaluated in lipopolysaccharide-stimulated murine peripheral blood lymphocytes assayed at various times following single or multiple injections of cyclophosphamide (3 mg/kg). Following a single injection, SCE levels in cultured lymphocytes from blood sampled at 5 min, 20 min, 35 min, 1 hr, and 3 hr postexposure were 17.1 +/- 2.0 (S.D.), 19.9 +/- 3.0, 19.3 +/- 1.8, 21.6 +/- 2.4, and 20.6 +/- 2.3, respectively. The control base-line SCE frequency was 11.2 +/- 1.2. The rapid initial increase in SCEs is consistent with the rapid increase reported previously in circulating active metabolites in rats following cyclophosphamide treatment. In peripheral blood lymphocytes cultured at 1 and 24 hr after serial injections of cyclophosphamide (3.0 mg/kg) two, four, and six times (every other day), a dose-related accumulation of SCEs occurred. Accumulation of SCEs was also observed in lymphocytes cultured at 24 and 72 hr following 12 multiple injections (three times weekly) of cyclophosphamide (3 mg/kg) (24.8 +/- 1.5 and 17.6 +/- 1.4, respectively) as compared to the single-injection group assayed at 24 and 72 hr postexposure (16.0 +/- 2.4 and 12.9 +/- 1.4, respectively). In the 12-multiple-injection study, an initial rapid decline at 72 hr was followed by a gradual decrease in SCE levels (1 week, 16.9 +/- 1.3; 2 weeks, 15.2 +/- 0.7; and 4 weeks, 13.4 +/- 1.1) which returned to near base-line (11.2 +/- 0.9) levels at 8 weeks. In the 12-multiple-injection study, successful growth of parallel concanavalin A-stimulated cultures was achieved only at 1, 2, and 4 weeks postexposure. Elevated SCE frequencies were observed at these intervals (16.2 +/- 2.1; 16.7 +/- 0.9; 14.2 +/- 0.3, respectively) relative to base-line SCE levels in concanavalin A-stimulated cells (12.1 +/- 1.8). The observed accumulation of SCEs with repeated exposure and persistence of SCE-inducing lesions parallel human data reported previously. The maximum induced (total minus baseline) SCE levels (10.2) observed in cultured lipopolysaccharide-stimulated lymphocytes from blood sampled at 1 hr after a single 3.0-mg/kg injection of cyclophosphamide were comparable or slightly higher than those (7.1) produced by the same dose of cyclophosphamide in murine bone marrow cells labeled with BrdUrd in vivo. However, in contrast to lymphocytes, bone marrow and alveolar macrophage cells did not accumulate SCEs upon repeated cyclophosphamide treatments.
在单次或多次注射环磷酰胺（3毫克/千克）后的不同时间，对脂多糖刺激的小鼠外周血淋巴细胞中的姐妹染色单体交换（SCE）反应进行了评估。单次注射后，暴露后5分钟、20分钟、35分钟、1小时和3小时采集的血液中培养的淋巴细胞的SCE水平分别为17.1±2.0（标准差）、19.9±3.0、19.3±1.8、21.6±2.4和20.6±2.3。对照基线SCE频率为11.2±1.2。SCE的快速初始增加与先前报道的环磷酰胺治疗后大鼠循环活性代谢物的快速增加一致。在连续注射环磷酰胺（3.0毫克/千克）两次、四次和六次（每隔一天）后1小时和24小时培养的外周血淋巴细胞中，出现了与剂量相关的SCE积累。与暴露后24小时和72小时测定的单次注射组相比（分别为16.0±2.4和12.9±1.4），在每周三次连续注射12次（3毫克/千克）环磷酰胺后24小时和72小时培养的淋巴细胞中也观察到SCE积累（分别为24.8±1.5和17.6±1.4）。在12次多次注射研究中，72小时时SCE水平最初快速下降，随后逐渐降低（1周时为16.9±1.3；2周时为15.2±0.7；4周时为13.4±1.1），8周时恢复到接近基线（11.2±0.9）水平。在12次多次注射研究中，仅在暴露后1、2和4周成功培养了平行的伴刀豆球蛋白A刺激的培养物。在这些时间间隔观察到SCE频率升高（分别为16.2±2.1；16.7±0.9；14.2±0.3），相对于伴刀豆球蛋白A刺激细胞中的基线SCE水平（12.1±1.8）。观察到的重复暴露后SCE积累以及SCE诱导损伤的持续存在与先前报道的人类数据相似。单次注射3.0毫克/千克环磷酰胺后1小时采集的血液中培养的脂多糖刺激淋巴细胞中观察到的最大诱导（总减去基线）SCE水平（10.2）与相同剂量环磷酰胺在体内用BrdUrd标记的小鼠骨髓细胞中产生的水平（7.1）相当或略高。然而，与淋巴细胞不同，骨髓和肺泡巨噬细胞在重复环磷酰胺治疗后不会积累SCE。
