Tumor necrosis factor alpha-mediated tumor regression by the in vivo transfer of genes into the artery that leads to tumors.
We report that tumor necrosis factor (TNF) alpha induced a strong antitumor immune reaction when it was produced in arteries leading to tumors by gene transfer in vivo. We used a mouse model carrying a sarcoma-180 tumor in the right footpad and injected the fusogenic liposomes encapsulating the human TNF-alpha gene into the right femoral artery. Under this condition, human TNF-alpha was detected only in the artery leading to the tumor and in the tumor. There was a significant regression in tumor growth when the TNF-alpha gene was delivered into the right femoral artery, with 4 of 11 mice completely cured. No regression was observed when the TNF-alpha gene was delivered into the left femoral artery or into the tumor or when the luciferase gene was administered. Tumor regression was inhibited by the injection of anti-TNF-alpha, anti-CD4, or anti-CD8 monoclonal antibody, and CD8+ T cells accumulated in the tumors of TNF-alpha-treated mice. These results suggest that TNF-alpha expressed locally in the arteries leading to tumors efficiently suppresses tumor growth through reinforcement of an antitumor immune reaction. The significance of this phenomenon for cancer gene therapy was discussed.
Mizuguchi
H
H
Faculty of Pharmaceutical Science, Osaka University, Suita, Japan.
Nakagawa
T
T
Toyosawa
S
S
Nakanishi
M
M
Imazu
S
S
Nakanishi
T
T
Tsutsumi
Y
Y
Nakagawa
S
S
Hayakawa
T
T
Ijuhin
N
N
Mayumi
T
T
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D004337:Drug Carriers / Q000008:administration & dosage; D005263:Femoral Artery; D018014:Gene Transfer Techniques; D008081:Liposomes / Q000008:administration & dosage; D051379:Mice; D012510:Sarcoma 180 / Q000098:blood supply / Q000276:immunology*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000494:pharmacology
D004337:Drug Carriers; D008081:Liposomes; D014409:Tumor Necrosis Factor-alpha