Electrophysiological study of the mechanism of diarrhea induced by camptothecin derivative

喜树碱衍生物致腹泻机制的电生理研究

• 批准号: 07457011
• 负责人: TAKEGUCHI Noriaki
• 金额: $ 0.58万
• 依托单位: TOYAMA MEDICAL AND PHARMACEUTICAL UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 1995
• 资助国家: 日本
• 起止时间: 1995 至 1996
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07457011/
• 关键词: camptpothecin; anti-tumor drug; diarrhed; thromboxane A_2; chloride ion secretion; irinotecan; トロンボキサンA_2; トロンボキサンAX_2; 制癌剤

Camptothecin is a plant alkaloid and a prototypic topoisomerase I-targeting drug. A camptothecin derivative, irinotecan, has a strong anti-cancer activity against many types of fumor such as colorectal, non-small cell lung, small cell lung, uterine cervical and ovarian cancers, and has recently become to be used clinically in U.S.A., Europe and Japan. One of major side-effects of this drug is a strong diarrhea. To decrease this side-effect in clinical use, it is necessary to know the mechanism that causes the diarrhea. Generally, diarrhed is caused by several different mechanisms including active secretion of electrolytes, especially Cl-ions.In the present study using isolated rat distal colons placed between Ussing chambers, we found that 1) the irinotecan causes the increase in the Cl- secretion. 2) the irinotecan-induced response is blocked by specific thromboxane A_2 (TXA_2) receptor antagonists and thromboxane synthase blockers, 3) the colon releases TXA_2 in response to irinotecan and 4) a stable TXA_2 analogue, STA_2, mimics the response of irinotecan. As the results, we found a new Cl- secretory mechanism that is mediated via TXA_2.

喜树碱是一种植物生物碱，是拓扑异构酶I靶向药物的原型。喜树碱衍生物伊立替康对多种类型的肿瘤如结肠直肠癌、非小细胞肺癌、小细胞肺癌、子宫颈癌和卵巢癌具有强的抗癌活性，最近在美国已开始临床使用，欧洲和日本。这种药的主要副作用之一是严重腹泻。为了减少临床使用中的副作用，有必要了解引起腹泻的机制。一般来说，肠梗阻是由几种不同的机制引起的，包括电解质的主动分泌，特别是Cl-离子。在本研究中，使用离体大鼠远端结肠放置在Ussing室之间，我们发现：1）伊立替康引起Cl-分泌增加。2)血栓素A_2（TXA_2）受体拮抗剂和血栓素合酶阻断剂可阻断伊立替康诱导的反应; 3）结肠对伊立替康的反应是释放TXA_2; 4）稳定的TXA_2类似物STA_2模拟伊立替康的反应。结果表明，脑组织Cl-的分泌可能是由TXA_2介导的.

项目成果

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Ikari 等人：“ATP、thasigargin 和 cAMP 增加 Ca^<2> 流入，激活三种不同的 Ca^<2> 流入途径。”

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Sakai, H. et al.: "Eicosanoid-mediated Cl^- secretion induced by the antitumor drug irinotecan (CRT-11) in the rat colon." Naunyn-Schmiedeberg's Archiev fur Pharmacology. 351. 309-314 (1995)

Sakai, H. 等人：“抗肿瘤药物伊立替康 (CRT-11) 在大鼠结肠中诱导类二十烷酸介导的 Cl^- 分泌。”

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Sakai, H.et al.：“GTP 结合蛋白介导的兔胃壁细胞中超氧阴离子的产生。”

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Suzuki, H. 等人：“胃囊泡的磷脂翻转酶活性。”