Department of Biomedical Sciences, University of Catania, Catania, Italy.
Mol Med Rep. 2011 Mar-Apr;4(2):203-8. doi: 10.3892/mmr.2010.408. Epub 2010 Dec 16.
Gene polymorphisms and mutations in various types of cancer may predict clinical response to chemotherapy and related toxicity, since they may affect the metabolism of the drugs commonly used in combination chemotherapy treatments. However, conflicting data have been generated on this subject. To elucidate this issue, this review discusses the clinical applications of several genetic polymorphisms in colorectal cancer patients treated with the most common agents alone or in combination. UDP-glucuronosyltransferase (UGT)1A1 is a conjugating biotransformation enzyme that plays a role in maintaining the levels of endogenous compounds (e.g., bilirubin) and in handling exogenous compounds, including carcinogens. It has been demonstrated that the UGT1A1*28 polymorphism plays a predictive role in patients administered an irinotecan-containing regimen. Polymorphisms in XPD (Lys751Gln), a member of the nucleotide excision repair pathway, negatively affect response to therapy, with oxaliplatin/5FU reducing the survival of the patient. A similar reaction has also been observed in patients with the XRCC1 Arg399Gln polymorphism, while patients with the GSTP1 Ile105Val polymorphism have an improved response to oxaliplatin/5FU therapy. Treatment with biological compounds such as cetuximab, an anti-epidermal growth factor receptor (EGFR) monoclonal antibody, has been shown to be effective only in colon cancer patients with wild-type K-Ras. Fc polymorphisms are associated with progression-free survival in patients treated with cetuximab. Another monoclonal antibody useful in the treatment of colon cancer is bevacizumab, a monoclonal antibody to vascular endothelial growth factor (VEGF); however, in some cases bevacizumab may cause deep vein thrombosis (DVP). In a related vein, our recent unpublished data show that the VEGF C936T polymorphism may increase the risk of DVP in cancer patients. In conclusion, this review indicates that certain polymorphisms increase the effectiveness of certain drugs, while others greatly enhance their toxicity. The study of the genetic 'habitus' therefore appears to be crucial for the development of tailored therapy for cancer patients.
基因多态性和突变在各种类型的癌症中可能预测对化疗的临床反应和相关毒性，因为它们可能影响联合化疗治疗中常用药物的代谢。然而，关于这个主题已经产生了相互矛盾的数据。为了解决这个问题，本综述讨论了几种遗传多态性在单独或联合使用最常见药物治疗的结直肠癌患者中的临床应用。UDP-葡萄糖醛酸基转移酶（UGT）1A1 是一种结合生物转化酶，在维持内源性化合物（如胆红素）的水平和处理外源性化合物（包括致癌物）方面发挥作用。已经证明，UGT1A1*28 多态性在接受伊立替康治疗方案的患者中具有预测作用。核苷酸切除修复途径的成员 XPD（Lys751Gln）中的多态性对治疗反应产生负面影响，奥沙利铂/5FU 降低患者的生存率。在 XRCC1 Arg399Gln 多态性的患者中也观察到类似的反应，而 GSTP1 Ile105Val 多态性的患者对奥沙利铂/5FU 治疗有更好的反应。曲妥珠单抗等生物化合物的治疗，一种抗表皮生长因子受体（EGFR）的单克隆抗体，已被证明仅对野生型 K-Ras 的结肠癌患者有效。Fc 多态性与接受曲妥珠单抗治疗的患者的无进展生存期相关。另一种在结肠癌治疗中有用的单克隆抗体是贝伐单抗，一种抗血管内皮生长因子（VEGF）的单克隆抗体；然而，在某些情况下，贝伐单抗可能会导致深静脉血栓形成（DVP）。在相关的方面，我们最近未发表的数据表明，VEGF C936T 多态性可能会增加癌症患者发生 DVP 的风险。总之，本综述表明，某些多态性增加了某些药物的有效性，而其他多态性则大大增加了它们的毒性。因此，研究遗传“习性”似乎对于为癌症患者制定个体化治疗方案至关重要。
