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.