Inhibitory effect of the salmosin gene transferred by cationic liposomes on the progression of B16BL6 tumors.
Salmosin is a novel disintegrin containing the Arg-Gly-Asp sequence that significantly inhibits platelet aggregation, basic fibroblast growth factor-induced endothelial cell proliferation, and tumor progression by antagonizing integrin-mediated cell interactions. Previously, it was shown that daily administration of salmosin was able to inhibit tumor-derived angiogenesis and adherence and proliferation of tumor cells, resulting in suppression of tumor progression. However, it is very difficult to maintain a therapeutic level of salmosin in the blood by systemic administration of the protein. Hence, an alternative strategy for antiangiogenic cancer therapy, based on the in vivo expression of the salmosin gene administered with cationic liposomes, was investigated. The salmosin peptides expressed in vitro inhibited the proliferation of bovine capillary endothelial cells in a dose-dependent manner, presumably as a result of inhibition of cell adhesion mediated via alpha(v)beta(3) integrin. Subcutaneous administration of the salmosin gene resulted in systemic expression of the gene product and concomitant inhibition of the growth of B16BL6 melanoma cells. Suppression of pulmonary metastases, verified by experimental and spontaneous metastasis models in mice, also resulted from salmosin gene treatment. These results suggest that administration of the salmosin gene complexed to cationic liposomes is effective in maintaining antiangiogenic salmosin at an effective therapeutic level and may be clinically applicable to anticancer gene therapy.
Kim
Soo In
SI
Department of Biomedical Laboratory Science and Institute of Health Science, Yonsei University, Wonju 220-710, South Korea.
Kim
Keun Sik
KS
Kim
Hong Sung
HS
Kim
Doo Sik
DS
Jang
Yangsoo
Y
Chung
Kwang Hoe
KH
Park
Yong Serk
YS
D000818:Animals; D002412:Cations; D002455:Cell Division / Q000235:genetics / Q000502:physiology; D003435:Crotalid Venoms / Q000096:biosynthesis / Q000235:genetics*; D018076:DNA, Complementary / Q000008:administration & dosage / Q000235:genetics; D005229:Fatty Acids, Monounsaturated / Q000008:administration & dosage; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000037:antagonists & inhibitors / Q000502:physiology; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D008081:Liposomes / Q000008:administration & dosage; D008546:Melanoma, Experimental / Q000235:genetics / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D000644:Quaternary Ammonium Compounds / Q000008:administration & dosage; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics; D014162:Transfection / Q000379:methods
D002412:Cations; D003435:Crotalid Venoms; D018076:DNA, Complementary; D005229:Fatty Acids, Monounsaturated; D008081:Liposomes; D000644:Quaternary Ammonium Compounds; D011994:Recombinant Proteins; C115393:salmosin; D016222:Fibroblast Growth Factor 2; C070046:1,2-dioleoyloxy-3-(trimethylammonium)propane