Intestinal alkalization as a possible preventive mechanism in irinotecan (CPT-11)-induced diarrhea

The therapeutic efficacy of irinotecan (CPT-11), a DNA topoisomerase inhibitor, is often limited by the induction of severe late-onset diarrhea. This prodrug and its active metabolite, 7-ethyl-10-hydroxy-camptothecin (SN-38), have a labile alpha-hydroxy-lactone ring that undergoes pH-dependent reversible hydrolysis. At physiological pH and higher, equilibrium favors the less toxic carboxylate form, whereas at acidic pH, the more potent lactone form is favored. We have reported previously that the initial uptake rate of CPT-11 and SN-38 by intestinal cells was significantly different between the respective lactone and carboxylate form. Results from the present study in HT-29 cells further demonstrate the correlation between the CPT-11/SN-38 initial uptake rate and the induced toxicity, cell cycle alteration, apoptosis, and colony-forming efficiency. The exposure of HT-29 cells to SN-38 for a limited period of time (