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ESTABLISHMENT OF PERSONALIZED CHEMOTHERAPY OF LUNG CANCER APPLYING PHARMACOGENOMICS

应用药物基因组学建立肺癌个体化化疗

基本信息

批准号：
14370196
负责人：
SHIMOKATA Kaoru
金额：
$ 9.02万
依托单位：
Nagoya University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14370196/
关键词：
cancer chemotherapy tailor-made therapy polymorphism enzyme clinical study irinotecan テーラード療法

项目摘要

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.

虽然伊立替康被广泛用作抗癌药物，但它会引起不可预测的严重毒性，偶尔会导致白细胞减少症或腹泻。伊立替康代谢形成活性SN-38，后者通过UDP-葡萄糖醛酸转移酶1A 1（UGT 1A 1）酶进一步结合和解毒。UCT 1A 1的遗传多态性将通过改变SN-38的生物利用度影响伊立替康毒性的个体间差异。我们研究了变异UGT 1A 1基因型是否具有较高的伊莫替康严重毒性风险。我们建议，UGT 1A 1基因型的测定可能是临床上有用的预测严重的毒性，伊立替康在癌症patient.We研究了UGT 1A 7基因的遗传多态性和伊立替康在日本癌症患者的毒性之间的关系。结果表明，UGT 1A 7基因型的测定不能用于预测伊立替康的严重毒性，我们建议根据UGT 1A 1的多态性进行伊立替康的I期研究^*28。名古屋大学的伦理委员会和IRB批准了该临床研究。当存在UGT 1A 1 ^*28的同源或异源多态性时，伊立替康剂量减半，未观察到严重副作用。确定UGT 1A 1 ^*28的多态性，既往伊立替康化疗将是有用的。