In vitro and in vivo evaluation of N,N,N-trimethylphytosphingosine-iodide (TMP) in liposomes for the treatment of angiogenesis and metastasis.
Phytosphingosine and methyl derivatives are important mediators on cellular processes, and are associated with cell growth and death. The antitumor activity of N,N,N-trimethylphytosphingosine-iodide (TMP) as a novel potent inhibitor of angiogenesis and metastasis was evaluated in B16F10 murine melanoma cells. The results indicated that TMP itself effectively inhibited in vitro cell migration, tube formation, and the expression of angiogenic factors as well as in vivo lung metastasis. However, TMP slightly suppressed in vivo experimental tumor metastasis in its free form and induced side effects including hemolysis and local side effects. Therefore, in an attempt to reduce the toxicity and the undesirable side effects of TMP, a liposomal formulation was prepared and tested for its effectiveness. TMP liposomes retained the effectiveness of TMP in vitro while side effects were reduced, and both in vivo experimental and spontaneous tumor metastasis were significantly suppressed. These results support the conclusion that TMP effectively inhibits in vitro angiogenesis as well as in vivo metastasis, and a liposomal formulation is more efficient delivery system for TMP treatment than solution.
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 151-742, South Korea.
Chung Kil
CK
Song
Ju-Hee
JH
Lee
Alexander
A
Jahn
Myeong Jun
MJ
Choi
Sung Keon
SK
Namgoong
Soon-Sun
SS
Hong
Saeho
S
Chong
Chang-Koo
CK
Shim
Suk-Jae
SJ
Chung
Dae-Duk
DD
Kim
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D008081:Liposomes; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology; D008546:Melanoma, Experimental / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000473:pathology; D000644:Quaternary Ammonium Compounds / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D013110:Sphingosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D008081:Liposomes; C577077:N,N,N-trimethylphytosphingosine; D000644:Quaternary Ammonium Compounds; D013110:Sphingosine