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Thromboxane A 2 , released by the anti‐ tumour drug irinotecan, is a novel stimulator of Cl − secretion in isolated rat colon
Author(s) -
Sakai Hideki,
Sato Takahiro,
Hamada Noriko,
Yasue Miyuki,
Ikari Akira,
Kakinoki Bunpei,
Takeguchi Noriaki
Publication year - 1997
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1111/j.1469-7793.1997.133bc.x
Subject(s) - irinotecan , thromboxane , thromboxane a2 , secretion , pharmacology , chemistry , endocrinology , medicine , receptor , colorectal cancer , platelet , cancer
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 A 2 (TXA 2 ) 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 A 2 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 TXA 2 in a concentration‐dependent manner from the isolated mucosa into the bathing solutions. 3 Furthermore, 9,11‐epithio‐11,12‐methano‐thromboxane A 2 (STA 2 ), a stable analogue of TXA 2 , induced Cl − secretion, which was almost completely inhibited by the TXA 2 receptor antagonists. 4 In single cells of isolated crypts, STA 2 depolarized the cell and increased the membrane conductance, indicating that STA 2 opened the apical Cl − channel of the crypt cells. 5 We conclude, therefore, that the irinotecan‐induced endogenous TXA 2 is a novel stimulant of the Cl − secretion from the crypt cells of distal colon.