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.