Theile Dirk, Grebhardt Sina, Haefeli Walter Emil, Weiss Johanna
Department of Internal Medicine VI, Clinical Pharmacology and Pharmacoepidemiology, University of Heidelberg, Im Neuenheimer Feld 410, D-69120 Heidelberg, Germany.
Biochem Pharmacol. 2009 Dec 1;78(11):1366-73. doi: 10.1016/j.bcp.2009.07.006. Epub 2009 Jul 19.
FOLFOX is a cytostatic drug combination for adjuvant treatment of colorectal cancer (CRC) consisting of 5-fluorouracil (5-FU), leucovorin, and oxaliplatin. The mechanism of synergistic interaction of these drugs is poorly understood and little is known concerning the role of drug transporters and the impact of oxaliplatin metabolites oxalate and dichloro-diaminocyclohexane platinum. We therefore investigated the influence of FOLFOX components on drug transporter expression by quantitative real-time polymerase chain reaction and on the efficacy of each FOLFOX component by proliferation assay in the CRC model cell line LS180. Control experiments with transporter over-expressing cell lines were used to assess the significance of important transporters for the cytostatic activity of FOLFOX components. Moreover, we assessed the pharmacological contribution of the oxalato-ligand to the effect of oxaliplatin. FOLFOX components led to several alterations in expression of drug transporters. For instance, 5-FU significantly suppressed ATP7B and human organic cation transporter 2 and increased multidrug resistance-associated protein (MRP) 2 mRNA expression (5.8-fold). This was accompanied by a significant sensitisation to oxaliplatin. Over-expression of certain ABC-transporters (BCRP/ABCG2, MRP2/ABCC2 or MRP3/ABCC3) was demonstrated to be beneficial for the efficacy of oxaliplatin. The results obtained indicate that both down- and up-regulations of drug transporters could favour synergistic action of this drug combination. Moreover, oxaliplatin metabolite oxalate seems to positively modulate oxaliplatin's action as elucidated by median effect analysis. In conclusion, we propose as one mechanism for FOLFOX synergism the 5-FU mediated suppression of ATP7B, the over-expression of glutathione exporters such as MRP2/ABCC2 and the decrease of glutathione levels by oxalate.
FOLFOX是一种用于辅助治疗结直肠癌（CRC）的细胞毒性药物组合，由5-氟尿嘧啶（5-FU）、亚叶酸和奥沙利铂组成。这些药物协同相互作用的机制尚不清楚，关于药物转运体的作用以及奥沙利铂代谢物草酸盐和二氯二氨基环己烷铂的影响也知之甚少。因此，我们通过定量实时聚合酶链反应研究了FOLFOX成分对药物转运体表达的影响，并通过在CRC模型细胞系LS180中的增殖试验研究了每种FOLFOX成分的疗效。使用转运体过表达细胞系进行对照实验，以评估重要转运体对FOLFOX成分细胞毒性活性的意义。此外，我们评估了草酸配体对奥沙利铂作用的药理学贡献。FOLFOX成分导致药物转运体表达出现多种变化。例如，5-FU显著抑制ATP7B和人类有机阳离子转运体2，并增加多药耐药相关蛋白（MRP）2的mRNA表达（5.8倍）。这伴随着对奥沙利铂的显著敏感性增加。某些ABC转运体（BCRP/ABCG2、MRP2/ABCC2或MRP3/ABCC3）的过表达被证明对奥沙利铂的疗效有益。获得的结果表明，药物转运体的下调和上调都可能有利于这种药物组合的协同作用。此外，如中位效应分析所阐明的，奥沙利铂代谢物草酸盐似乎对奥沙利铂的作用有正向调节作用。总之，我们提出FOLFOX协同作用的一种机制是5-FU介导的ATP7B抑制、谷胱甘肽转运体如MRP2/ABCC2的过表达以及草酸盐导致的谷胱甘肽水平降低。
