Gene therapy of orthotopic hepatocellular carcinoma in rats using adenovirus coding for interleukin 12.
The use of gene therapy to enhance antitumor immunity has emerged as a promising procedure to fight cancer. In this study we have tested the ability of an adenovirus carrying interleukin 12 (IL-12) gene (AdCMVIL-12) to eliminate tumoral lesions in 3 animal models of orthotopic hepatocellular carcinoma (HCC). Intratumoral injection of AdCMVIL-12 in animals with a single big tumor nodule implanted in the liver resulted in significant inhibition of tumor growth in a dose-dependent manner. Fifty percent of animals that received a dose of 5 x 10(9) plaque-forming units, showed complete regression of the tumor 2 weeks after treatment. In animals with 2 independent tumor nodules in the left liver lobe, injection in only one of them of 5 x 10(9) pfu AdCMVIL-12 induced, 15 days after therapy, complete regression of 50% of treated tumors and also of 50% of untreated lesions, with 60% long-term survival. Rats that were tumor free after therapy with AdCMVIL-12 showed protection against tumor rechallenge. A group of rats received the carcinogen diethylnitrosamine and developed multiple hepatic dysplasic nodules of 1 to 5 mm in diameter. These animals were treated by intrahepatic artery injection of either AdCMVIL-12 (5 x 10(9) pfu) or control vector. In this model AdCMVIL-12 induced complete tumor regression in 20% of treated rats and inhibited tumor growth in 60% of cases with an increase in rat survival. Activation of natural killer (NK) cells and inhibition of angiogenesis were found to be antitumor mechanisms set in motion by AdCMVIL-12. Our data indicate that experimental HCC can be efficiently treated by intratumoral or intravascular injection of adenovirus expressing IL-12.
Barajas
M
M
Division of Hepatology and Gene Therapy, Department of Medicine, School of Medicine and Clinica Universitaria, University of Navarra, Pamplona, Spain.
Mazzolini
G
G
Genové
G
G
Bilbao
R
R
Narvaiza
I
I
Schmitz
V
V
Sangro
B
B
Melero
I
I
Qian
C
C
Prieto
J
J
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D002273:Carcinogens; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000628:therapy*; D002460:Cell Line; D004052:Diethylnitrosamine; D015316:Genetic Therapy; D015552:Injections, Intralesional; D018664:Interleukin-12 / Q000235:genetics*; D007694:Killer Cells, Natural / Q000502:physiology; D008113:Liver Neoplasms / Q000139:chemically induced / Q000628:therapy*; D008297:Male; D009378:Neoplasms, Multiple Primary / Q000628:therapy; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D051381:Rats; D011915:Rats, Inbred BUF; D017208:Rats, Wistar
D002273:Carcinogens; D018664:Interleukin-12; D004052:Diethylnitrosamine