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 reverse this effect and increase a tumor's sensitivity to chemotherapy. In vivo, intravenous sphingomyelin (10 mg/day, 7 days) potentiated 5-fluorouracil chemotherapy (0.45 mg/day, 5 days) when co-administered to HT29 human colonic xenograft-bearing nude mice. In vitro, sphingomyelin (SM) at its maximum tolerated concentration increased 5-fluorouracil and doxorubicin sensitivity of HCT15 and MOSER (1 mg/ml SM) and LS174T and SW480 human colonic tumor cells (0.1 mg/ml) approximately 100-300%. At 1 mg/ml SM, however, no effect was seen using HT29, LoVo and WiDr cells. There was no sensitization of normal human umbilical cord endothelial cells. Thus, sphingomyelin co-administration may be one method to improve the selective efficacy of chemotherapy in some tumors, possibly through enhancement of the apoptotic response.
Modrak
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Garden State Cancer Center, 520 Belleville Avenue, Belleville, New Jersey 07109, USA. dmodrak.gscc@worldnet.att.net
Lew
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Goldenberg
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Blumenthal
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D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D003110:Colonic Neoplasms / Q000188:drug therapy*; D004195:Disease Models, Animal; D004357:Drug Synergism; D005472:Fluorouracil / Q000627:therapeutic use*; D006801:Humans; D007275:Injections, Intravenous; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D013109:Sphingomyelins / Q000627:therapeutic use*; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D000964:Antimetabolites, Antineoplastic; D013109:Sphingomyelins; D005472:Fluorouracil