Thromboxane A₂, released by the anti-tumour drug irinotecan, is a novel stimulator of Cl^- secretion in isolated rat colon

1. A camptothecin derivative, irinotecan (Cpt-11), is a topoisomerase I inhibitor and has a strong activity against a broad range of human cancer. One of the side-effects of this drug is diarrhoea. Here, we tried to determine the mediator of the irinotecan-induced Cl^- secretion which may underlie this diarrhoea, using isolated mucosae of rat distal colon. 2. Irinotecan increased Cl^- secretory current in a concentration-dependent manner across the mucosa, set between Ussing chambers. Thromboxane A₂ (TXA₂) has not been reported to date as a physiological stimulant of Cl^- secretion in the distal colon. However, the major part of the present irinotecan-induced current was inhibited by selective thromboxane A₂ receptor antagonists (KW-3635 and ONO-3708), and a selective thromboxane synthase inhibitor (Y-20811). In fact, we found that irinotecan stimulated the release of TXA₂ in a concentration-dependent manner from the isolated mucosa into the bathing solutions. 3. Furthermore, 9,11-epithio-11,12-methano-thromboxane A₂ (STA₂), a stable analogue of TXA₂, induced Cl^- secretion, which was almost completely inhibited by the TXA₂ receptor antagonists. 4. In single cells of isolated crypts, STA₂ depolarized the cell and increased the membrane conductance, indicating that STA₂ opened the apical Cl^- channel of the crypt cells. 5. We conclude, therefore, that the irinotecan-induced endogenous TXA₂ is a novel stimulant of the Cl^- secretion from the crypt cells of distal colon.