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 (<2 h) was sufficient to induce these events. Because the decreased initial uptake of
SN-38 carboxylate resulted in a reduced cellular toxicity, we postulated that the CPT-11-induced
diarrhea was preventable by influencing the equilibrium toward the carboxylate form and, thus, reducing its intestinal uptake. In the golden Syrian hamster model, p.o.
sodium bicarbonate supplementation (5 mg/ml in
drinking water) led to alkalization of the intestinal contents. In addition, this alkalization resulted in the reduction of the histopathological damage to the mucosa of the small and large intestine, as well as a 20% reduction of the intestinal
SN-38 lactone concentration of animals receiving
CPT-11 (20-50 mg/kg x 7 days). Taken together, these results from in vitro and in vivo studies support intestinal alkalization by
sodium bicarbonate supplementation as a preventive mechanism against CPT-11-induced
diarrhea. In addition, this provides a strong rationale for the usage of this measure as an adjunct to
CPT-11 treatment.