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.
Wildiers
Hans
H
Laboratory of Experimental Oncology (LEO), University Hospital Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium. hans.wildiers@uz.kuleuven.ac.be
Ahmed
Bisan
B
Guetens
Gunter
G
De Boeck
Gert
G
De Bruijn
Ernst A
EA
Landuyt
Willy
W
Van Oosterom
Allan T
AT
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D004347:Drug Interactions; D000077146:Irinotecan; D009536:Niacinamide / Q000494:pharmacology*; D011355:Prodrugs / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D012208:Rhabdomyosarcoma / Q000097:blood / Q000188:drug therapy*
D000972:Antineoplastic Agents, Phytogenic; D011355:Prodrugs; D009536:Niacinamide; D000077146:Irinotecan; D002166:Camptothecin