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

肺癌患者拓扑异构酶I基因突变与盐酸伊立替康疗效的关系

• 批准号: 15590826
• 负责人: KOBAYASHI Hirosuke
• 金额: $ 2.05万
• 依托单位: Kitasato University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15590826/
• 关键词: malignancy; polymorphism; lung cancer; chemotherapy agent; drug resistance; drug toxicity

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.

本研究在日本志愿者中研究了与化疗药物伊立替康（CPT-11）的耐药和代谢相关的拓扑异构酶I（TOP I）、羧酸酯酶1&2（CES 1&2）和UDP-葡萄糖醛酸基转移酶1A1（UGT1A1）的多态性，以及TOP I多态性在肺癌中的作用。 还对组织进行了研究，试图为癌症的定制治疗做出贡献。在这项研究中，获得了以下结果。1）在日本成年人以及未经治疗的肺癌组织中，没有观察到据报道与 CPT-11 耐药性相关的 TOP I 外显子的多态性。2）在 126 个样本中，有 2 个在 CES 2 外显子中检测到杂合突变。 CES 2 在癌细胞中将 CPT-11 转化为 SN38，其中 SN38 已知对癌细胞具有毒性。这种突变率非常低，不会对CPT-11对患者癌细胞的有效性差异产生太大影响。3)在CES 1外显子中检测到多个多态性。 CES 1 在肝细胞中将 CPT-11 转化为 SN38。这种突变率非常高，被认为是导致患者毒性差异的原因之一。4)本研究受试者中UGT1A1*28的纯合突变率为2%。已知 UGT1A1 通过与葡萄糖醛酸结合而使 SN38 形成可溶形式，并且这种突变已知会增强 SN38 的毒性。据怀疑，与美洲、欧洲和非洲人群相比，除印度人外的亚洲人群中很少出现与这种酶活性相关的毒性。

项目成果

Electromagnetic Interference of Implantable Unipolar Cardiac Pacemakers by an Induction Oven.

电磁炉对植入式单极心脏起搏器的电磁干扰。

• 发表时间: 2005
• 期刊: PACE 28
• 作者: Hirose M;Hida M;Sato E;Kokubo K;Nie M;Kobayashi H
• 通讯作者: Kobayashi H

Characteristics of auditory alarms for medical equipment and future issues.

医疗设备听觉警报的特点和未来的问题。

• 发表时间: 2005
• 期刊: Journal of Clinical Engineering 30
• 作者: Hirose M;Sato E;Taguchi M;Kokubo K;Kobayashi H;Watanabe S
• 通讯作者: Watanabe S

Biweekly therapy for non-small cell lung cancer using cisplatin, paclitaxel and gemcitabine.

使用顺铂、紫杉醇和吉西他滨每两周治疗非小细胞肺癌。

• 发表时间: 2006
• 期刊: Kitasato Med J 35(In press)
• 作者: Tanaka N;Honma K;Masubuchi T;Tanimura S;Yokoba M;Mitsufuji H;他
• 通讯作者: 他

Local and systemic expression of inducible nitric oxide synthase in comparison with that of cyclooxygenase-2 in rat carrageenin-induced pleurisy.

大鼠角叉菜胶诱导的胸膜炎中诱导型一氧化氮合酶的局部和全身表达与环氧合酶-2 的比较。

• 发表时间: 2005
• 期刊: Nitric Oxide-Biol Chem 12
• 作者: Fujisawa H;Nakagawa S;Ohkubo Y;Matsui M;Yamaguchi S;Kawamura M;Hatanaka K;Kawakubo Y;Hiramoto Y;Kobayashi H;Harada Y
• 通讯作者: Harada Y

IL-10 induces inhibitory C/EBP through STAT-3 and represses HIV-1 transcription in Macrophages

IL-10 通过 STAT-3 诱导抑制性 C/EBP 并抑制巨噬细胞中的 HIV-1 转录

• 发表时间: 2005
• 期刊: Am.J.Respir.Cell Mol.Biol 33
• 作者: Tanaka N;Hoshino Y;Gold J;Hoshino S;Martiniuk F;Kurata T;Pine R;Levy D;Rom WN;Weiden M
• 通讯作者: Weiden M