THE ROLE OF GENETIC POLYMORPHISMS OF DRUG TRANSPORTER GENES FOR THE TREATMENT OF LUNG CANCER

伊立替康意外引起重度、偶尔致死性的白细胞减少症或腹泻毒性。三磷酸腺苷结合盒转运蛋白（ABCC 2）将伊立替康及其代谢产物从肝细胞转运至胆汁。我们在120例日本癌症患者中评估了ABCC 2的变异形式是否会影响患者间对伊立替康毒性的敏感性变化。通过PCR片段的直接测序进行ABCC 2基因分型。我们在ABCC 2中发现了五个多态性。ABCC 2 2375 A>G是一个新的多态性，天冬氨酸取代甘氨酸。单变量logistic回归分析发现，严重毒性与ABCC 2多态性携带之间无显著相关性。结果表明，ABCC 2的核酸多态性的测定将不会用于预测伊立替康的严重毒性。另一方面，有机阴离子转运多肽C（OATP-C）在SN-38从门静脉血转运到肝细胞中发挥重要作用。OATP-C^*1 a、OATP-C^* 1 b和OATP-C^*15的等位基因频率分别为0.31、0.58和0.11。逻辑回归分析未显示严重毒性的发生与携带OATP-C^*15之间存在任何显著相关性。OATP-C^*15和UGT 1A 1 ^*28的双重变体倾向于与重度毒性的发生相关，尽管其不具有统计学显著性。

Irinotecan unexpectedly causes severe, occasionally fatal, toxicity of leukopenia or diarrhea. Adenosine triphosphate-binding cassette transporters (ABCC2) transport irinotecan and its metabolites from hepatocytes to the bile. We assessed whether variant forms of ABCC2 would affect inter-patient variations in sensitivity to irinotecan toxicity in 120 Japanese patients with a cancer. The genotyping of ABCC2 was performed by direct sequencing of the PCR fragment. We found five polymorphisms in ABCC2. ABCC2 2375A>G is a new polymorphism, substituting aspartic acid for glycine. Univariate logistic regression analysis found no significant association between severe toxicities and carrying at ABCC2 polymorphisms. The results suggested that the determination of nucleic polymorphisms of ABCC2 would not be useful for predicting severe toxicities by irinotecan. On the other hand, organic anion transporting polypeptide C (OATP-C) plays a major role in the transport of SN-38 from portal venous blood to hepartocytes. The allele frequencies of OATP-C^*1 a, OATP-C^*1b, and OATP-C^*15 were 0.31, 0.58, and 0.11, respectively. Logistic regression analysis did not show any significant association between the occurrence of severe toxicity and carrying OATP-C^*15. The double variants for OATP-C^*15 and UGT1A1 ^*28 tended to be associated with the occurrence of severe toxicity, although it was not statistically significant.