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

奥沙利铂用于基于5-氟尿嘧啶的联合化疗。有趣的是，据报道，奥沙利铂治疗后，dUTR基因表达受到p53稳定的抑制，但详细的分子机制尚不清楚。我们发现，当结肠癌细胞用顺铂和卡铂处理时，没有观察到抑制。由于奥沙利铂及其类似物达铂可抑制dUTR表达，因此由1，2-二氨基环己烷（DACH）载体配体诱导的DNA损伤反应对于抑制作用至关重要。我们的研究结果表明，奥沙利铂可以通过调节胸苷酸生物合成相关基因的表达来增强5-氟尿嘧啶的细胞毒性。

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.