Lentz Frederike, Tran Agnès, Rey Elisabeth, Pons Gérard, Tréluyer Jean-Marc
Service de Pharmacologie, Hôpital Saint Vincent de Paul, avenue Denfert-Rochereau, Paris, 75014, France.
Am J Pharmacogenomics. 2005;5(1):21-33. doi: 10.2165/00129785-200505010-00002.
Hepatic metastases occur in about half of patients with colorectal cancer. Since hepatic metastases are often not accessible for surgery, chemotherapy of metastases is important. The most commonly used chemotherapy drugs for hepatic metastases are fluorouracil, irinotecan, and oxaliplatin. Several enzymes are known to be involved in the catabolism and anabolism of these drugs, and the activity of these enzymes varies greatly between individuals. The causes of this variation include genetic polymorphisms, different regulation between normal and cancer tissue, and the influence of chemotherapy on enzyme expression. The varying enzyme activity may have an important effect on the outcome of chemotherapy. Several studies confirm the influence of the activity of thymidylate synthase, thymidine phosphorylase and dihydropyrimidine dehydrogenase on the outcome of fluorouracil therapy for colorectal cancer, with higher enzyme activities predicting lower treatment efficacy. Although fewer studies are available regarding therapy of hepatic metastases, the same relationship between thymidylate synthase activity and outcome of fluorouracil therapy observed for primary colorectal cancer was found. For the other two enzymes, only a few studies are available, but the results indicate similarly that higher enzyme activity seems to be disadvantageous. The enzymes responsible for the activation, metabolism and mechanism of action of irinotecan, namely carboxylesterase 2, cytochrome P450 (CYP) 3A4, uridine diphosphate glucuronosyltransferase isoform 1A1 (UGT1A1), and topoisomerase-I, also exhibit variable interindividual activity. Thus, there may be an association between enzyme activity and response to therapy. For instance, in patients with colorectal cancer, higher enzyme activity of topoisomerase-I seems to be predictive of a better response to irinotecan. CYP3A4 and UGT1A1 activity levels might be predictive of irinotecan toxicity rather than efficacy. The degradation of oxaliplatin is independent of potentially varying enzyme activity, but for this drug, the DNA repair enzyme ERCC1 may influence the survival time after chemotherapy. Taken together, the available data indicate the importance of the different enzyme activities on the outcome of chemotherapy of hepatic metastases in colorectal cancer. More information is needed, especially for the newer drugs irinotecan and oxaliplatin. However, the existing data are very promising in respect to the potential to guide dose and drug selection for more efficient and less toxic chemotherapy of hepatic metastases.
大约一半的结直肠癌患者会发生肝转移。由于肝转移灶通常无法进行手术切除，因此对转移灶进行化疗很重要。用于肝转移的最常用化疗药物是氟尿嘧啶、伊立替康和奥沙利铂。已知几种酶参与这些药物的分解代谢和合成代谢，并且这些酶的活性在个体之间差异很大。这种差异的原因包括基因多态性、正常组织和癌组织之间的不同调节以及化疗对酶表达的影响。酶活性的变化可能对化疗结果产生重要影响。多项研究证实胸苷酸合成酶、胸苷磷酸化酶和二氢嘧啶脱氢酶的活性对结直肠癌氟尿嘧啶治疗结果有影响，酶活性越高，治疗效果越低。虽然关于肝转移治疗的研究较少，但在原发性结直肠癌中观察到的胸苷酸合成酶活性与氟尿嘧啶治疗结果之间的关系同样存在。对于其他两种酶，仅有少数研究，但结果同样表明酶活性越高似乎越不利。负责伊立替康激活、代谢和作用机制的酶，即羧酸酯酶2、细胞色素P450（CYP）3A4、尿苷二磷酸葡萄糖醛酸转移酶同工酶1A1（UGT1A1）和拓扑异构酶-I，也表现出个体间活性的差异。因此，酶活性与治疗反应之间可能存在关联。例如，在结直肠癌患者中，拓扑异构酶-I的酶活性较高似乎预示着对伊立替康的反应更好。CYP3A4和UGT1A1的活性水平可能预示伊立替康的毒性而非疗效。奥沙利铂的降解与潜在变化的酶活性无关，但对于这种药物，DNA修复酶ERCC1可能影响化疗后的生存时间。综上所述，现有数据表明不同酶活性对结直肠癌肝转移化疗结果的重要性。需要更多信息，特别是关于新型药物伊立替康和奥沙利铂的信息。然而，现有数据在指导肝转移更高效、低毒化疗的剂量和药物选择方面具有很大潜力，前景十分广阔。
