Tumor necrosis factor alpha-gene therapy for an established murine melanoma using RGD (Arg-Gly-Asp) fiber-mutant adenovirus vectors.
Although adenovirus vectors (Ad) provide high-level transduction efficacy to many cell types, extremely high doses of Ad are required for sufficient gene transduction into several tumors, including melanoma. Here, we demonstrated that the expression of coxsackie-adenovirus receptor, a primitive Ad-receptor, was very low in murine and human melanoma cells. We also found that fiber-mutant Ad containing the Arg-Gly-Asp (RGD) sequence in the fiber knob remarkably augmented gene transduction efficacy in melanoma cells by targeting alpha(v)-integrins. In addition, intratumoral injection of RGD fiber-mutant Ad containing the tumor necrosis factor alpha gene (Ad-RGD-TNFalpha) revealed dramatic anti-tumor efficacy through hemolytic necrosis in an established murine B16 BL6 melanoma model. Ad-RGD-TNFalpha required one-tenth the dosage of Ad-TNFalpha to induce an equal therapeutic effect. These results suggest that alpha(v)-integrin-targeted Ad will be a very powerful tool for the advancement of melanoma gene therapy.
Okada
Yuka
Y
Department of Pharmaceutics, School of Pharmaceutical Sciences, Mukogawa Women's University, Koshien, Nishinomiya, Hyogo 663-8179, Japan.
Okada
Naoki
N
Nakagawa
Shinsaku
S
Mizuguchi
Hiroyuki
H
Takahashi
Koichi
K
Mizuno
Nobuyasu
N
Fujita
Takuya
T
Yamamoto
Akira
A
Hayakawa
Takao
T
Mayumi
Tadanori
T
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D045744:Cell Line, Tumor; D006224:Cricetinae; D004770:Enterovirus / Q000235:genetics; D005434:Flow Cytometry; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D039564:Integrin alphaV / Q000378:metabolism; D007763:Lac Operon; D008545:Melanoma / Q000378:metabolism / Q000628:therapy*; D008546:Melanoma, Experimental / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D009336:Necrosis; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D011485:Protein Binding; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
D000911:Antibodies, Monoclonal; D039564:Integrin alphaV; D009842:Oligopeptides; D014409:Tumor Necrosis Factor-alpha; D049452:Green Fluorescent Proteins; C047981:arginyl-glycyl-aspartic acid