Sphingomyelin enhances chemotherapy efficacy and increases apoptosis in human colonic tumor xenografts.
Evidence suggests that ceramide, generated from a distinct subcellular pool of sphingomyelin (SM) by the action of sphingomyelinases, may be used by cells to propagate apoptotic signals in response to a variety of cytotoxic agents. Since most tumor cells have altered lipid metabolism, it is possible that the intracellular pool of SM used for signaling is decreased. To overcome this, we have attempted to increase the SM content of all intracellular compartments with exogenous SM and examined the impact on 5-fluorouracil (5FU) and irinotecan chemosensitivity. Our data suggest that the efficacy of these two chemotherapeutics for the treatment of HT-29, HCT15 and GW-39 human colonic tumor xenografts can be enhanced by the use of exogenous SM. Furthermore, this enhancement may be due to a reversal of the attenuation of the apoptotic signal found in cancer cells without inducing significant hematopoietic, hepatic or renal toxicity.
Modrak
David E
DE
Garden State Cancer Center, Belleville, NJ 07109, USA. dmodrak.gscc@att.net
Rodriguez
Marisol D
MD
Goldenberg
David M
DM
Lew
Walter
W
Blumenthal
Rosalyn D
RD
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D002945:Cisplatin / Q000494:pharmacology / Q000627:therapeutic use; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D004195:Disease Models, Animal; D004357:Drug Synergism; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D000077146:Irinotecan; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D015398:Signal Transduction / Q000187:drug effects; D013109:Sphingomyelins / Q000494:pharmacology* / Q000627:therapeutic use*; D013997:Time Factors; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D013109:Sphingomyelins; D000077146:Irinotecan; D002945:Cisplatin; D005472:Fluorouracil; D002166:Camptothecin