Sphingomyelin potentiates chemotherapy of human cancer xenografts

We propose that one manifestation of altered sphingolipid metabolism within tumor cells may be a reduced sensitivity to anti-cancer therapies because of an inability to produce a sufficient apoptotic signal via sphingomyelin hydrolysis to ceramide, If so, then sphingomyelin administration could reve rse this effect and increase a tumor's sensitivity to chemotherapy, In vivo intravenous sphingomyelin (10 mg/day, 7 days) potentiated B-fluorouracil c hemotherapy (0.45 mg/day, 5 days) when co-administered to HT29 human coloni c xenograft-bearing nude mice. In vitro, sphingomyelin (SM) at its maximum tolerated concentration increased 5-fluorouracil and doxorubicin sensitivit y of HCT15 and MOSER (1 mg/ml SM.) and LS174T and SW480 human colonic tumor cells (0.1 mg/ml) approximately 100-300%. At I mg/ml SM, however, no effec t was seen using HT29, LoVo and WiDr cells. There was no sensitization of n ormal human umbilical cord endothelial cells. Thus, sphingomyelin coadminis tration may be one method to improve the selective efficacy of chemotherapy in some tumors, possibly through enhancement of the apoptotic response. (C ) 2000 Academic Press.