Inhibition of B16BL6 tumor progression by coadministration of recombinant angiostatin K1-3 and endostatin genes with cationic liposomes.
Transfection of the antiangiogenic angiostatin and endostatin genes was shown to be an alternative to high-dose administration of angiostatin or endostatin proteins for cancer therapy. We have systematically investigated whether coadministration of the mouse angiostatin kringle 1-3 gene (pFLAG-AngioK1/3) and the endostatin gene (pFLAG-Endo) complexed with cationic liposomes exhibits enhanced therapeutic efficacy. In vitro, the coexpressed mixture of angiostatin K1-3 and endostatin more effectively reduced angiogenesis in chorioallantoic membranes than either angiostatin K1-3 or endostatin alone. In vivo, subcutaneous co-administration of pFLAG-AngioK1/3 and pFLAG-Endo lipoplexes more effectively inhibited vascularization in Matrigel plugs implanted in mice than either one alone. Additionally, subcutaneous administration of these genes inhibited the growth and formation of pulmonary metastases of B16BL6 melanoma cells in mice. Compared to treatment with an empty vector, treatment with pFLAG-AngioK1/3 plus pFLAG-Endo inhibited 81% of tumor growth, while treatment with pFLAG-AngioK1/3 or pFLAG-Endo inhibited tumor growth 70 and 69%, respectively. Cotreatment with the two plasmids after primary tumor excision induced a 90% inhibition of pulmonary metastases versus 79% for pFLAG-AngioK1/3 or 80% for pFLAG-Endo individually. These results suggest that combined administration of angiostatin K1-3 and endostatin genes complexed with cationic liposomes may be an innovated antiangiogenic strategy for cancer therapy.
Kim
Keun Sik
KS
Department of Biomedical Laboratory Science and Institute of Health Science, Yonsei University, Wonju 220-710, Republic of Korea.
Kim
Hong Sung
HS
Park
Jin Seu
JS
Kwon
Young Guen
YG
Park
Yong Serk
YS
D043168:Angiostatins / Q000235:genetics* / Q000627:therapeutic use*; D000818:Animals; D015153:Blotting, Western; D002412:Cations; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002642:Chick Embryo; D003094:Collagen / Q000737:chemistry / Q000494:pharmacology; D018076:DNA, Complementary / Q000378:metabolism; D018450:Disease Progression; D004338:Drug Combinations; D043169:Endostatins / Q000235:genetics* / Q000627:therapeutic use; D006801:Humans; D007797:Laminin / Q000737:chemistry / Q000494:pharmacology; D008081:Liposomes / Q000378:metabolism; D008546:Melanoma, Experimental; D051379:Mice; D008810:Mice, Inbred C57BL; D015233:Models, Statistical; D009369:Neoplasms / Q000473:pathology / Q000628:therapy*; D010957:Plasmids / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011509:Proteoglycans / Q000737:chemistry / Q000494:pharmacology; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics*; D013997:Time Factors; D014162:Transfection
D002412:Cations; D018076:DNA, Complementary; D004338:Drug Combinations; D043169:Endostatins; D007797:Laminin; D008081:Liposomes; D011509:Proteoglycans; D011994:Recombinant Proteins; C059485:matrigel; D043168:Angiostatins; D003094:Collagen