Unexpected interactions between nicotinamide and CPT-11 in a rhabdomyosarcoma tumor model

We investigated the potential chemosensitizing effect of nicotinamide on CPT-11, and the relationship between nicotinamide and CPT-11, intratumoral drug uptake in syngeneic rhabdomyosarcoma tumors in rats. Pretreatment with nicotinamide, known to improve tumor oxygenation, perfusion and radiotherapy effect, only caused a minor increase in tumor growth delay. To our surprise, intratumoral uptake of CPT-11 and its active metabolite SN-38 decreased significantly between 19% and 43%. This discrepancy suggests that the potential chemosensitizing effect of nicotinamide, seen in other studies, is based on a direct effect on tumor cells rather than on an increased delivery of anticancer drugs. A second finding is that plasma levels of CPT-11 and SN-38 respectively increase and decrease after nicotinamide exposure, suggesting inhibition of carboxylesterase, which is necessary for the conversion of CPT-11 to its active metabolite SN-38. Great care is required when combining nicotinamide with anticancer drugs, since unexpected pharmacokinetic and pharmacodynamic alterations might occur.