Possible mechanisms of diarrheal side effects associated with the use of a novel chemotherapeutic agent, flavopiridol.
The novel cyclin-dependent kinase inhibitor flavopiridol has recently completed Phase I trials for the treatment of refractory neoplasms. The dose-limiting toxicity observed with this agent was severe diarrhea. Because the compound otherwise showed promise, the present study sought to determine possible mechanisms underlying the diarrheal side effects. Flavopiridol was tested for its ability to modify chloride secretory responses of the human colonic epithelial cell line, T84. Studies were conducted in vitro in modified Ussing chambers. High concentrations of flavopiridol (10(-4) M), above those likely to be clinically relevant, had a direct stimulatory effect on chloride secretion, probably ascribable to an increase in cyclic AMP. Lower, clinically relevant concentrations of flavopiridol (10(-6) M) had no effect on chloride secretion by themselves but potentiated responses to the calcium-dependent secretagogue, carbachol. The drug also potentiated responses to thapsigargin and taurodeoxycholate and reversed the inhibitory effects of carbachol and epidermal growth factor on calcium-dependent chloride secretion. Pretreatment with the cyclic AMP-dependent secretagogue, forskolin, potentiated responses to flavopiridol, but not vice versa. Thus, diarrheal side effects induced by flavopiridol are likely multifactorial in origin and may involve interactions with endogenous secretagogues such as acetylcholine and bile acids. A better understanding of the diarrhea induced by flavopiridol should allow optimization of therapy with this otherwise promising drug and/or the development of related agents with improved toxicity profiles.
Department of Medicine, University of California, San Diego, School of Medicine, 92103, USA.
M E
ME
Kahn
A
A
Senderowicz
E A
EA
Sausville
K E
KE
Barrett
D000970:Antineoplastic Agents / Q000009:adverse effects*; D002217:Carbachol / Q000494:pharmacology; D018118:Chloride Channels / Q000187:drug effects / Q000378:metabolism; D002712:Chlorides / Q000378:metabolism*; D018679:Cholinergic Agonists / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D003106:Colon / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D003967:Diarrhea / Q000139:chemically induced* / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005419:Flavonoids / Q000009:adverse effects*; D006801:Humans; D066298:In Vitro Techniques; D007413:Intestinal Mucosa / Q000378:metabolism*; D010880:Piperidines / Q000009:adverse effects*
D000970:Antineoplastic Agents; D018118:Chloride Channels; D002712:Chlorides; D018679:Cholinergic Agonists; D005419:Flavonoids; D010880:Piperidines; D005576:Colforsin; C077990:alvocidib; D004815:Epidermal Growth Factor; D002217:Carbachol; D000242:Cyclic AMP; D018844:Cyclin-Dependent Kinases