Eradication of hepatocellular carcinoma xenografts by radiolabelled, lipiodol-inducible gene therapy.
The promoter region of the early-growth response-1(Egr-1) gene has been shown to be activated by external radiation, thus making a selective tumoricidal effect possible. A previous experiment showed that the Egr-1 promoter can be activated by internal radiation using radioisotopes as well as external radiation. Internal radiation using I-131 lipiodol (I-131-Lip) has been established as one of the most useful therapeutic strategies against hepatoma. We herein linked the Egr-1 promoter to the herpes simplex virus-thymidine kinase (HSV-TK) gene, and investigated its efficacy in hepatoma gene therapy in combination with I-131-Lip. A luciferase assay showed the Egr-1-promoter activity to be markedly increased in hepatoma tissue specimens in an I-131-dose-dependent manner, whereas a less than two-fold increase in this activity was observed in other organs. In addition, the radioactivity derived from I-131 was selectively accumulated in the tumor tissue specimens. To examine the efficacy of EgrTK/ganciclovir (GCV) gene therapy in vivo, subcutaneous hepatoma xenografts in nude mice were transfected using a hemagglutinating virus of Japan (HVJ)-liposome vector. Complete tumor regression was observed in all the EgrTK-transfected tumors following combination treatment with I-131-Lip and GCV 42 days after treatment without any side effects (n=8). In contrast, the tumors continued to grow in all control mice (n=10). Furthermore, the serum alpha-fetoprotein levels decreased in the combination therapy group, while they increased in the controls. In conclusion, these data indicate that Egr-1 promoter-based gene therapy combined with internal radiation has a selective effect on hepatoma tumors while also showing an improved in vivo efficacy. This combination therapy might, therefore, be an effective human hepatoma gene therapy, even in advanced multiple cases.
Kawashita
Y
Y
Department of Transplantation and Digestive Surgery, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.
Ohtsuru
A
A
Miki
F
F
Kuroda
H
H
Morishita
M
M
Kaneda
Y
Y
Hatsushiba
K
K
Kanematsu
T
T
Yamashita
S
S
D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use; D006528:Carcinoma, Hepatocellular / Q000097:blood / Q000628:therapy* / Q000821:virology; D003131:Combined Modality Therapy; D004307:Dose-Response Relationship, Radiation; D051766:Early Growth Response Protein 1 / Q000032:analysis / Q000235:genetics*; D015774:Ganciclovir / Q000627:therapeutic use; D005818:Genetic Engineering; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D007457:Iodine Radioisotopes / Q000008:administration & dosage; D007459:Iodized Oil; D008113:Liver Neoplasms / Q000097:blood / Q000628:therapy* / Q000821:virology; D008114:Liver Neoplasms, Experimental; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011401:Promoter Regions, Genetic; D018139:Simplexvirus / Q000201:enzymology; D013194:Staining and Labeling; D013937:Thymidine Kinase / Q000235:genetics; D014161:Transduction, Genetic; D014183:Transplantation, Heterologous; D000509:alpha-Fetoproteins / Q000032:analysis
D000998:Antiviral Agents; D051766:Early Growth Response Protein 1; D007457:Iodine Radioisotopes; D000509:alpha-Fetoproteins; D007459:Iodized Oil; D013937:Thymidine Kinase; D015774:Ganciclovir