Possible mechanisms of diarrheal side effects associated with the use of anovel chemotherapeutic agent, flavopiridol

The novel cyclin-dependent kinase inhibitor flavopiridol has recently compl eted Phase I trials for the treatment of refractory neoplasms. The dose-lim iting toxicity observed with this agent was severe diarrhea, Because the co mpound otherwise showed promise, the present study sought to determine poss ible mechanisms underlying the diarrheal side effects. Flavopiridol was tes ted for its ability to modify chloride secretory responses of the human col onic epithelial cell line, T-84, Studies were conducted in vitro in modifie d Ussing chambers. High concentrations of flavopiridol (10(-4) M), above th ose likely to be clinically relevant, had a direct stimulatory effect on ch loride 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 calci um-dependent secretagogue, carbachol, The drug also potentiated responses t o thapsigargin and taurodeoxycholate and reversed the inhibitory effects of carbachol and epidermal growth factor on calcium-dependent chloride secret ion. Pretreatment with the cyclic AMP-dependent secretagogue, forskolin, po tentiated responses to flavopiridol, but not vice versa, Thus, diarrheal si de effects induced by flavopiridol are likely multifactorial in origin and may involve interactions with endogenous secretagogues such as acetylcholin e and bile acids. A better understanding of the diarrhea induced by flavopi ridol should allow optimization of therapy with this otherwise promising dr ug and/or the development of related agents with improved toxicity profiles .