Electrophysiological study of the mechanism of diarrhea induced by camptothecin derivative

喜树碱是一种植物生物碱，也是一种拓扑异构酶I靶向药物。喜树碱衍生物伊立替康对结直肠癌、非小细胞肺癌、小细胞肺癌、子宫颈癌和卵巢癌等多种肿瘤有很强的抗癌活性，近年来已在美国、欧洲和日本等地用于临床。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这种副作用，有必要了解引起腹泻的机制。一般情况下，腹泻是由几种不同的机制引起的，包括电解质的活跃分泌，特别是氯离子的分泌。在本研究中，我们使用放置在Ussing腔之间的大鼠远端结肠，我们发现：1)伊立替康导致氯离子分泌的增加。2)特异性血栓素A_2(TXA_2)受体拮抗剂和血栓素合成酶阻断剂可阻断伊立替康的反应；3)伊立替康使结肠释放TXA_2；4)稳定的TXA_2类似伊立替康。因此，我们发现了一种新的氯离子分泌机制，这种机制是通过TXA2介导的。

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.