Mechanisms of dUTPase downregulation by oxaliplatin and its applications to combination chemotherapy

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Oxaliplatin is used in 5-fluorouracil-based combination chemotherapy. Interestingly, the dUTPase gene expression was reportedly suppressed by p53 stabilization after oxaliplatin treatment, however, the detailed molecular mechanisms were unclear. We found that the suppression was not observed when colon cancer cells were treated with cisplatin and carboplatin. Because oxaliplatin and its analog, dachplatin, can suppress dUTPase expression, the DNA damage response induced by 1,2-diaminocyclohexane (DACH) carrier ligand would be critical for the suppression effect. Our results suggested that oxaliplatin could enhance the cytotoxicity of 5-fluorouracil by regulating the expression of the genes that are implicated in thymidylate biosynthesis.