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

奥沙利铂用于5-氟尿嘧啶联合化疗。有趣的是，据报道，奥沙利铂治疗后，dUTPase基因表达被p53稳定化抑制，然而，详细的分子机制尚不清楚。我们发现用顺铂和卡铂治疗结肠癌细胞时没有观察到这种抑制。由于奥沙利铂及其类似物达克铂可以抑制dUTPase的表达，1,2-二氨基环己烷（DACH）载体配体诱导的DNA损伤反应是抑制效果的关键。我们的研究结果表明，奥沙利铂可以通过调节与胸苷酸生物合成有关的基因的表达来增强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.