title: Cooperative inhibitory effect of n,n,n-trimethylsphingosine and sphingosine-1-phosphate, co-incorporated in liposomes, on b16 melanoma cell metastasis - cell-membrane signaling as a target in cancer-therapy .4.
abstract: Two N-methylated derivatives of sphingosine (Sph), N,N-dimethyl-Sph (DMS) and N,N,N-trimethyl-Sph (TMS), have been shown to stereospecifically inhibit activity of protein kinase C and other kinases essential for active proliferation of tumor cells, as well as for activation of platelets and endothelial cells (ECs). DMS and TMS thereby inhibit tumor growth in vivo, and TMS inhibits in vivo metastatic potential of B16 melanoma cells. When TMS was administered in liposomes, its drug efficacy was increased and its undesirable side-effects were greatly reduced (Park YS, er al, Cancer Res 54: 2213, 1994). Sph-1-P, long known as the initial catabolite of Sph metabolism, has aroused considerable interest recently because of its inhibitory effect on cell motility (Sadahira Y, et al, Proc Natl Acad Sci USA 89: 9686, 1992). We now report that liposomes containing both TMS and Sph-1-P, in comparison to liposomes containing TMS or Sph-1-P alone, exert a much stronger inhibitory effect on B16 melanoma cell metastasis. This is ascribable to their inhibitory effect on tumor cell invasiveness through motility inhibition, in conjunction with the previously-observed inhibitory effect of TMS on activation of platelets and ECs. Furthermore, the liposomal formulation resulted in prolonged circulation time of both TMS and Sph-1-P in blood, and consequent higher concentration of these compounds in tumor tissues.
authors.affiliation: BIOMEMBRANE INST,SEATTLE,WA 98119. UNIV WASHINGTON,DEPT PATHOBIOL,SEATTLE,WA 98195. UNIV WASHINGTON,DEPT MICROBIOL,SEATTLE,WA 98195.
authors.forename: Y
authors.initials: Y
authors.lastname: Park
authors.forename: F
authors.initials: F
authors.lastname: Ruan
authors.forename: S
authors.initials: S
authors.lastname: Hakomori
authors.forename: Y
authors.initials: Y
authors.lastname: Igarashi