van Duijn-Goedhart A, Zdzienicka M Z, Sankaranarayanan K, van Buul P P
MGC, LUMC--Department of Radiation Genetics and Chemical Mutagenesis, Sylvius Laboratory, Leiden University, Wassenaarseweg 72, 2333 AL Leiden, The Netherlands.
Mutat Res. 2000 Nov 20;471(1-2):95-105. doi: 10.1016/s1383-5718(00)00122-4.
To shed light on the mechanism underlying the cellular response to the radiomimetic agents calicheamicin Y(1)(1) (CAL) and neocarzinostatin (NCS), several hamster cell mutants defective in different DNA repair pathways were used. Two X-ray sensitive Chinese hamster V79 mutant cell lines, XR-V9B and V-E5 were studied for their response to the induction of cell killing, micronuclei, and G2-chromosomal aberrations relative to that of parental wild-type cells. In addition, effects of CAL and NCS on bleomycin sensitive BL-V40 cells and on UV sensitive V-H1 cells were analyzed. In general, the radiosensitive cell lines showed the highest sensitivities to CAL and NCS, but also the other mutants demonstrated differences in their responses compared to wild-type cells. With respect to cell killing, expressed as D(10)-value, enhanced sensitivities of mutants with factors up to 4.4 were recorded. For the induction of micronuclei (MN) and chromosomal aberrations (CA) all cell lines, including the parental cells, show a steep increase in the frequencies at the lowest tested doses and a leveling off at higher concentrations. Probably toxic effects at the higher exposure levels are responsible for these biphasic dose effect curves. Enhanced sensitivities of the various mutants were primarily observed at the higher exposure levels. With respect to the induction of MN increased sensitivities up to a factor of 18.1 were observed for the radiosensitive mutants, whereas for CA the mutant cell lines showed a variation from resistance (0.3) of VH-1 cells up to a 3.8-fold higher sensitivity to the radiomimetic agents. However, at the lowest tested concentrations for both MN and CA, the differences between the sensitive mutants and wild-type clearly diminished, suggesting the existence of residual and/or alternative DNA repair pathways in these mutants.
为了阐明细胞对拟放射剂加利车霉素Y(1)(1)（CAL）和新制癌菌素（NCS）产生反应的潜在机制，研究人员使用了几种在不同DNA修复途径中存在缺陷的仓鼠细胞突变体。研究了两种对X射线敏感的中国仓鼠V79突变细胞系XR-V9B和V-E5相对于其亲本野生型细胞在细胞杀伤、微核和G2染色体畸变诱导方面的反应。此外，还分析了CAL和NCS对博来霉素敏感的BL-V40细胞和紫外线敏感的V-H1细胞的影响。总体而言，放射敏感细胞系对CAL和NCS表现出最高的敏感性，但与野生型细胞相比，其他突变体在反应上也存在差异。就以D(10)值表示的细胞杀伤而言，记录到突变体的敏感性增强，增强因子高达4.4。对于微核（MN）和染色体畸变（CA）的诱导，所有细胞系，包括亲本细胞，在最低测试剂量下频率急剧增加，在较高浓度下趋于平稳。可能是较高暴露水平下的毒性作用导致了这些双相剂量效应曲线。各种突变体的敏感性增强主要在较高暴露水平下观察到。就MN的诱导而言，放射敏感突变体的敏感性增强高达18.1倍，而对于CA，突变细胞系对拟放射剂的敏感性从VH-1细胞的抗性（0.3）到高3.8倍不等。然而，在MN和CA的最低测试浓度下，敏感突变体与野生型之间的差异明显减小，这表明这些突变体中存在残余和/或替代的DNA修复途径。
