Liposomal N,N,N-trimethylsphingosine (TMS) as an inhibitor of B16 melanoma cell growth and metastasis with reduced toxicity and enhanced drug efficacy compared to free TMS: cell membrane signaling as a target in cancer therapy III.
We demonstrated previously that N,N,N-trimethylsphingosine (TMS) and N,N-dimethylsphingosine (DMS), but not unsubstituted sphingosine, produce significant inhibitory effects on in vivo growth of human tumor cells in nude mice (K. Endo et al., Cancer Res., 51: 1613-1618, 1991) and on metastasis of B16 melanoma cells in syngeneic mice (H. Okoshi et al., Cancer Res., 51: 6019-6024, 1991). These observations were attributed to inhibition by TMS or DMS of protein kinase C activity and tumor cell-dependent platelet activation. TMS yields a more stable aqueous solution than DMS, and its antitumor effect is more reproducible. However, dosages of both TMS and DMS required to produce significant antitumor or antimetastasis effects are high (several injections of 0.1-0.3 mg/mouse). At these dosages, TMS treatment (by tail vein injection) often produced the undesirable side effects of hemolysis and hemoglobinuria. We now report that TMS incorporated into liposomes with egg phosphatidylcholine and cholesterol had no hemolytic effect, yet was more potent than free TMS in suppressing B16 melanoma cell growth and metastasis. Biodistribution assay revealed that, compared to free TMS, liposomal TMS was accumulated in tumor tissue at higher concentrations and had longer circulation half-life. These factors could explain the higher antitumor efficacy of liposomal TMS.
Park
Y S
YS
Biomembrane Institute, Seattle, Washington 98119.
Hakomori
S
S
Kawa
S
S
Ruan
F
F
Igarashi
Y
Y
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000633:toxicity; D002250:Carbon Radioisotopes; D002455:Cell Division / Q000187:drug effects; D002462:Cell Membrane / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004337:Drug Carriers; D005260:Female; D006461:Hemolysis; D006801:Humans; D007205:Indium Radioisotopes; D008081:Liposomes; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis; D010974:Platelet Aggregation / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D013110:Sphingosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity; D014018:Tissue Distribution
D000970:Antineoplastic Agents; D002250:Carbon Radioisotopes; D004337:Drug Carriers; D007205:Indium Radioisotopes; D008081:Liposomes; C071600:N,N,N-trimethylsphingosine; D013110:Sphingosine