Schlade-Bartusiak Kamila, Stembalska-Kozlowska Agnieszka, Bernady Monika, Kudyba Marta, Sasiadek Maria
Department of Genetics, Wroclaw Medical University, Marcinkowskiego 1, 50-368 Wroclaw, Poland.
Mutat Res. 2002 Jan 15;513(1-2):75-81. doi: 10.1016/s1383-5718(01)00288-1.
Genetic instability resulting from the disturbances in various mechanisms of DNA-repair is the characteristic feature of cancer cells. One of the possibilities to evaluate the effectiveness of DNA-repair system is the adaptive response (AR) analysis. The AR is a phenomenon by which cells exposed to low, non-genotoxic doses of a mutagen become significantly resistant to a subsequent higher dose of the same or another genotoxic agent. Generally, it is postulated that AR is related to a reduction of damage by the induction of free radical detoxification and/or DNA-repair systems. The existence of various DNA-repair mechanisms poses the question whether there are differences in AR induced by chemicals causing DNA-damage that requires different pathways for its repair. In this paper we present the study on the AR induced by two chemical mutagens, bleomycin (BLM) and mitomycin C (MMC), which differ in their action on DNA. BLM is a radiomimetic agent causing mainly single-strand breaks (SSB) and double-strand breaks (DSB) and, thus, inducing chromosomal aberrations (CA). MMC is a potent bifunctional mutagen acting as an alkylating agent, causing DNA cross-links and inducing sister chromatid exchanges (SCEs). The protective effect induced by low doses of tested chemicals was analysed in whole blood human lymphocytes using cytogenetic endpoints (CA for BLM and SCE for MMC, respectively) as a measure of chromosomal instability. There was a significant difference between the protective effects induced by BLM and MMC in the lymphocytes of the same group of donors. The pre-treatment with a low dose of BLM-induced almost 50% decrease in the frequency of CA induced by challenging dose (CD), while the protective effect of MMC was below 20%. The higher AR induced by BLM may be related to the repair processing of BLM-induced DNA-damages. There was also a variability in ARs among individuals, which may reflect the differences in individual DNA-repair capacity.
由DNA修复的各种机制紊乱导致的基因不稳定是癌细胞的特征。评估DNA修复系统有效性的一种可能性是适应性反应（AR）分析。适应性反应是一种现象，即暴露于低剂量、非基因毒性诱变剂的细胞会对随后更高剂量的相同或另一种基因毒性剂产生显著抗性。一般来说，推测适应性反应与通过诱导自由基解毒和/或DNA修复系统减少损伤有关。各种DNA修复机制的存在提出了一个问题，即导致DNA损伤的化学物质诱导的适应性反应是否存在差异，而这些损伤需要不同的修复途径。在本文中，我们展示了对两种化学诱变剂博来霉素（BLM）和丝裂霉素C（MMC）诱导的适应性反应的研究，这两种诱变剂对DNA的作用不同。博来霉素是一种放射模拟剂，主要导致单链断裂（SSB）和双链断裂（DSB），从而诱导染色体畸变（CA）。丝裂霉素C是一种强效双功能诱变剂，作为烷基化剂起作用，导致DNA交联并诱导姐妹染色单体交换（SCE）。使用细胞遗传学终点（分别针对博来霉素的CA和针对丝裂霉素C的SCE）作为染色体不稳定性的指标，分析了低剂量受试化学物质在全血人淋巴细胞中诱导的保护作用。同一组供体的淋巴细胞中，博来霉素和丝裂霉素C诱导的保护作用存在显著差异。低剂量博来霉素预处理可使激发剂量（CD）诱导的CA频率降低近50%，而丝裂霉素C的保护作用低于20%。博来霉素诱导的较高适应性反应可能与博来霉素诱导的DNA损伤的修复过程有关。个体之间的适应性反应也存在差异，这可能反映了个体DNA修复能力的差异。
