A camptothecin derivative, irinotecan (Cptâ11), is a topoisomerase I inhibitor and has a strong activity against a broad range of human cancer. One of the sideâeffects of this drug is diarrhoea. Here, we tried to determine the mediator of the irinotecanâinduced Clâ secretion which may underlie this diarrhoea, using isolated mucosae of rat distal colon.
Irinotecan increased Clâ secretory current in a concentrationâdependent manner across the mucosa, set between Ussing chambers. Thromboxane A2 (TXA2) has not been reported to date as a physiological stimulant of Clâ secretion in the distal colon. However, the major part of the present irinotecanâinduced current was inhibited by selective thromboxane A2 receptor antagonists (KWâ3635 and ONOâ3708), and a selective thromboxane synthase inhibitor (Yâ20811). In fact, we found that irinotecan stimulated the release of TXA2 in a concentrationâdependent manner from the isolated mucosa into the bathing solutions.
Furthermore, 9,11âepithioâ11,12âmethanoâthromboxane A2 (STA2), a stable analogue of TXA2, induced Clâ secretion, which was almost completely inhibited by the TXA2 receptor antagonists.
In single cells of isolated crypts, STA2 depolarized the cell and increased the membrane conductance, indicating that STA2 opened the apical Clâ channel of the crypt cells.
We conclude, therefore, that the irinotecanâinduced endogenous TXA2 is a novel stimulant of the Clâ secretion from the crypt cells of distal colon.