Electroporation-mediated tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/Apo2L gene therapy for hepatocellular carcinoma.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)/Apo2 ligand (Apo2L) has been identified as important in promoting programmed cell death in breast and colon cancer xenografts. More importantly, normal liver tissue appears not to be susceptible to the cytotoxic effects of TRAIL/Apo2L, although activation of the related Fas ligand receptor system is known to promote massive liver apoptosis terminating in fulminant hepatitis. In the present study, we investigated the therapeutic potential of TRAIL/Apo2L gene therapy in hepatocellular carcinoma (HCC) and evaluated its side effects in an immune-competent mouse model. Intratumoral administration of the TRAIL/Apo2L vector by electroporation elevated serum TRAIL/Apo2L through at least day 28 after gene therapy and significantly inhibited the growth not only of the HCC directly administered TRAIL/Apo2L vector, but also of distant subcutaneous HCC. In addition, intratumoral administration of the TRAIL/Apo2L vector inhibited spontaneous lung metastasis. Serum alanine aminotransferase was mildly elevated by TRAIL/Apo2L gene therapy, but without showing such histological signs as TUNEL staining. These results demonstrate that TRAIL/Apo2L gene therapy for HCC by electroporation in vivo is efficient without significant side effects, and is thus promising for use in future clinical trials.
Yamashita
Yo-Ichi
Y
Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. yamashi@surg2.med.kyushu-u.ac.jp
Shimada
Mitsuo
M
Tanaka
Shinji
S
Okamamoto
Masahiro
M
Miyazaki
Jun-Ichi
J
Sugimachi
Keizo
K
D000818:Animals; D051017:Apoptosis Regulatory Proteins; D006528:Carcinoma, Hepatocellular / Q000628:therapy*; D018274:Electroporation / Q000379:methods*; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D008175:Lung Neoplasms / Q000628:therapy*; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000627:therapeutic use; D051379:Mice; D008809:Mice, Inbred C3H; D009362:Neoplasm Metastasis; D011233:Precipitin Tests; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000627:therapeutic use
D051017:Apoptosis Regulatory Proteins; D008562:Membrane Glycoproteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505654:Tnfsf10 protein, mouse; D014409:Tumor Necrosis Factor-alpha