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

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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.