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A comparative analysis of the mutagenicity of platinum-containing chemotherapeutic agents reveals direct and indirect mutagenic mechanisms
Mutagenesis ( IF 2.7 ) Pub Date : 2021-01-19 , DOI: 10.1093/mutage/geab005
Bernadett Szikriszt 1 , Ádám Póti 1 , Eszter Németh 1 , Nnennaya Kanu 2 , Charles Swanton 2 , Dávid Szüts 1
Affiliation  

Platinum-based drugs are a mainstay of cancer chemotherapy. However, their mutagenic effect can increase tumour heterogeneity, contribute to the evolution of treatment resistance and also induce secondary malignancies. We coupled whole genome sequencing with phenotypic investigations on two cell line models to compare the magnitude and examine the mechanism of mutagenicity of cisplatin, carboplatin and oxaliplatin. Cisplatin induced significantly more base substitution mutations than carboplatin or oxaliplatin when used at equitoxic concentrations on human TK6 or chicken DT40 cells, and also induced the highest number of short insertions and deletions. The analysis of base substitution spectra revealed that all three tested platinum drugs elicit both a direct mutagenic effect at purine dinucleotides, and an indirect effect of accelerating endogenous mutagenic processes, whereas the direct mutagenic effect appeared to correlate with the level of DNA damage caused as assessed through histone H2AX phosphorylation and single-cell agarose gel electrophoresis, the indirect mutagenic effects were equal. The different mutagenicity and DNA-damaging effect of equitoxic platinum drug treatments suggest that DNA damage independent mechanisms significantly contribute to their cytotoxicity. Thus, the comparatively high mutagenicity of cisplatin should be taken into account in the design of chemotherapeutic regimens.

中文翻译:

含铂化疗药物致突变性的比较分析揭示了直接和间接的致突变机制

铂类药物是癌症化疗的中流砥柱。然而,它们的诱变作用会增加肿瘤的异质性,导致治疗耐药性的演变,并诱发继发性恶性肿瘤。我们将全基因组测序与两种细胞系模型的表型研究相结合,以比较顺铂、卡铂和奥沙利铂的致突变性大小并检查其机制。当在人 TK6 或鸡 DT40 细胞上以等毒浓度使用时,顺铂诱导的碱基取代突变明显多于卡铂或奥沙利铂,并且还诱导最多数量的短插入和缺失。碱基取代光谱分析表明,所有三种测试的铂类药物都对嘌呤二核苷酸产生直接诱变作用,和加速内源性诱变过程的间接效应,而直接诱变效应似乎与通过组蛋白 H2AX 磷酸化和单细胞琼脂糖凝胶电泳评估的 DNA 损伤水平相关,间接诱变效应是相同的。等毒铂类药物治疗的不同致突变性和 DNA 损伤作用表明,DNA 损伤独立机制显着促进了它们的细胞毒性。因此,在设计化疗方案时应考虑顺铂相对较高的致突变性。间接诱变效应是相同的。等毒铂类药物治疗的不同致突变性和 DNA 损伤作用表明,DNA 损伤独立机制显着促进了它们的细胞毒性。因此,在设计化疗方案时应考虑顺铂相对较高的致突变性。间接诱变效应是相同的。等毒铂类药物治疗的不同致突变性和 DNA 损伤作用表明,DNA 损伤独立机制显着促进了它们的细胞毒性。因此,在设计化疗方案时应考虑顺铂相对较高的致突变性。
更新日期:2021-01-19
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