ESTABLISHMENT OF PERSONALIZED CHEMOTHERAPY OF LUNG CANCER APPLYING PHARMACOGENOMICS

虽然伊立替康被广泛用作抗癌药物，但它会导致白细胞减少症或腹泻的不可预测的严重毒性，有时甚至是致命的毒性。伊立替康被代谢成具有活性的SN-38，并被UDP-葡萄糖醛酸基转移酶1A1(UGT1A1)酶进一步结合和解毒。UCT1A1的遗传多态将通过改变SN-38的生物利用度来影响伊立替康的毒性的内部变异。我们调查了变异的UGT1A1基因型是否会因imotcan的严重毒性而面临更高的风险。我们认为检测UGT1A1基因可能对预测伊立替康对癌症患者的严重毒性有一定的临床意义。结果提示，检测UGT1A7基因不能用于预测伊立替康的严重毒性。根据UGT1A1^*28基因的多态性，我们建议伊立替康进行一期研究。名古屋大学伦理委员会和IRB批准了这项临床研究。当UGT1A1^*28存在同型或杂型多态时，伊立替康的剂量减少一半，且未见严重副作用。UGT1A1^*28基因多态性检测，有伊立替康化疗史者优先。

Although irinotecan is widely used as an anticancer drug, it causes unpredictably severe, occasionally fatal toxicity of leukopenia or diarrhea. Irinotecan is metabolized to form active SN-38,which is further conjugated and detoxified by UDP-glucuronosyltransferase1A1(UGT1A1) enzyme. Genetic polymorphism of the UCT1A1 would affect an interindivisual variation of the toxicity by irinotecan via the alternation of bioavailability of SN-38. We investigated whether the variant UGT1A1 genotypes would be at higher risk for severe toxicity by imotcan. We suggested that determination of the UGT1A1 genotypes might be clinically useful for predicting severe toxicity by irinotecan in cancer patients.We studied the relationship between genetic polymorphisms of the UGT1A7 gene and irinotecan toxicity in Japanese cancer patients. The results suggested that determination of UGT1A7 genotypes would not be useful for predicting severe toxicity of irinotecan.We proposed phase 1 study of irinotecan according to the polymorphism of UGT1A1^*28. The Ethical Committee and IRB in the Nagoya University approved the clinical study. When there are homo-or hetero-polymorphism of UGT1A1^*28,the dose of irinotecan was decreased at half level, and no severe side effects were not observed. Determination of polymorphism of UGT1A1^*28,prior irinotecan chemotherapy would be useful.