Relationship between Topoisomerase I gene mutation in patients with lung cancer and the effect of irinotecan hydrochloride

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In this study, polymorphisms of topoisomerase I (TOP I), carboxylesterase 1&2 (CES 1&2) and UDP-glucuronosyltransferase 1A1(UGT1A1), which are all related to the resistance and metabolism of chemotherapy agent irinotecan (CPT-11), were investigated in Japanese volunteers, and the polymorphism of TOP I in lung cancer tissue was also investigated, in an attempt to contribute to tailor-made treatment of cancers.In this study, following findings were obtained.1)No polymorphism in exons of TOP I, which are reported to be related to CPT-11 resistance, was observed in Japanese adults as well as in untreated lung cancer tissues.2)In 2 out of 126 specimen, heterozygous mutation was detected in CES 2 exons. CES 2 converts CPT-11 to SN38 in cancer cells, where SN38 is known to be toxic in cancer cells. This mutation rate is very low, and will not contribute much to the difference in effectiveness of CPT-11 to cancer cells in patients.3)There were several polymorphisms detected in CES 1 exons. CES 1 converts CPT-l1 to SN38 in liver cells. This mutation rate is very high, and is considered to contribute to the difference in toxicity in patients..4)The homozygous mutation in UGT1A1*28 was 2% in the subjects in this study. UGT1A1 is known to make SN38 soluble form by conjugating it with glucuronic acid, and this mutation is known to enhance the toxicity of SN38. It is suspected that the toxicity related to this enzyme activity is seldom in Asian population except Indians, compared to American, European and African population.