Ehling U H, Neuhäuser-Klaus A
Institut für Sügetiergenetik, Gesellschaft für Strahlen- und Umweltforschung, Neuherberg, Federal Republic of Germany.
Mutat Res. 1988 May;199(1):21-30. doi: 10.1016/0027-5107(88)90226-6.
Cyclophosphamide is the most widely used antineoplastic agent. It is also used to condition patients for bone-marrow transplantations. Because of the general interest of this compound we initiated a systematic study of the induction of dominant-lethal and specific-locus mutations in male mice. In addition, we investigated the induction of specific-locus mutations by the combined treatment of cyclophosphamide and ionizing radiation. A dose of 40 mg/kg bw of cyclophosphamide caused dominant-lethal mutations in male mice only in the 1st and 2nd week after treatment. A dose of 120 mg/kg induced dominant-lethal mutations in the mating intervals 1-21 days posttreatment. No dominant lethal mutations were observed after the 3rd week. The same differential spermatogenic response was observed for the induction of specific-locus mutations. Cyclophosphamide induced recessive mutations exclusively in spermatozoa and spermatids. No mutations were recovered from treated spermatocytes and spermatogonia. In contrast to cyclophosphamide, radiation induces specific-locus mutations in all germ-cell stages. The pretreatment with cyclophosphamide 24 h before radiation enhanced the frequency of specific-locus mutations in spermatogonia. The distribution of the observed mutations among the 7 loci and their viability supports the hypothesis that these mutations were induced by radiation rather than by cyclophosphamide. The compound causes an immediate inhibition of DNA and RNA synthesis in spermatogonia. The inhibition very likely interferes with the repair process. The disturbance of the repair process is probably the cause of the synergistic effect for the induction of specific-locus mutations in spermatogonia of mice after pretreatment with cyclophosphamide 24 h before irradiation.
环磷酰胺是使用最广泛的抗肿瘤药物。它也用于为骨髓移植患者进行预处理。由于对这种化合物的广泛关注，我们开展了一项关于雄性小鼠显性致死和特定位点突变诱导的系统研究。此外，我们还研究了环磷酰胺与电离辐射联合处理对特定位点突变的诱导作用。剂量为40mg/kg体重的环磷酰胺仅在处理后的第1周和第2周导致雄性小鼠出现显性致死突变。剂量为120mg/kg在处理后1 - 21天的交配间隔中诱导出显性致死突变。第3周后未观察到显性致死突变。在特定位点突变的诱导方面也观察到了相同的生精差异反应。环磷酰胺仅在精子和精细胞中诱导隐性突变。未从处理后的精母细胞和精原细胞中检测到突变。与环磷酰胺不同，辐射在所有生殖细胞阶段都能诱导特定位点突变。在辐射前24小时用环磷酰胺预处理可提高精原细胞中特定位点突变的频率。观察到的突变在7个位点中的分布及其生存能力支持了这些突变是由辐射而非环磷酰胺诱导的这一假设。该化合物可立即抑制精原细胞中的DNA和RNA合成。这种抑制很可能干扰了修复过程。修复过程的紊乱可能是在照射前24小时用环磷酰胺预处理后小鼠精原细胞中特定位点突变诱导产生协同效应的原因。
