Cisplatin is more mutagenic than carboplatin or oxaliplatin at equitoxic concentrations

Abstract

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 understand 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. Assessment through histone H2AX phosphorylation and single cell agarose gel electrophoresis suggested that cisplatin caused more DNA damage than carboplatin or oxaliplatin. 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 correlated with the level of DNA damage caused, the indirect mutagenic effects were equal. The different mutagenicity and DNA damaging effect of equitoxic platinum drug treatments suggests 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.

Reassessment of the Efficacy of Carboplatin for Metastatic Urothelial Carcinoma in the Era of Immunotherapy: A Systematic Review and Meta-analysis

“…However, cisplatin and carboplatin differ in terms of the extent of DNA adduct formation, which has been hypothesized to account for differences in their efficacy [27]. Further, cisplatin exhibits greater mutagenicity than carboplatin and is more likely to damage the DNA [28]. Carboplatin is less likely to cause renal damage due to its structural configuration; the structure is unlikely to form a substrate for organic cation transporter 2, the transporter involved in cisplatin uptake, thus making its uptake by proximal tubular cells unlikely [29].…”