Therapeutic effect of intravenous interferon gene delivery with naked plasmid DNA in murine metastasis models.
Interferons (IFNs) exhibit pleiotropic biological activities that are considered to play important roles in tumor suppression and rejection. Therefore, IFN genes are promising for in vivo cytokine gene therapy targeted against tumors. In the present study, we evaluated the efficacy of hydrodynamics-based IFN gene transfer for tumor treatment, in which the naked pDNA encoding IFN-beta or IFN-gamma was administered into the tail vein of mice following portal vein (liver metastasis), tail vein (lung metastasis), or subcutaneous injection (subcutaneous tumor) of mouse colon carcinoma CT-26 cells. A substantial amount of IFN was soon markedly expressed in the liver and a transient increase in IFN activity was detected in the circulation. This procedure caused transgene-specific IFN production with little induction of other proinflammatory cytokines. In the liver metastasis experiment, the mice treated with IFN-expressing pDNA displayed a profound reduction in liver metastasis and a prolonged survival. Administration of the pDNA at an earlier stage of metastasis was more crucial for the antitumor effect. Similar tumor suppression was seen in the lung metastasis experiment. These therapeutic effects were more marked with IFN-beta-expressing pDNA treatment than with IFN-gamma-expressing pDNA treatment. On the other hand, subcutaneous CT-26 tumor growth was hardly affected by pDNA administration. These results suggest that the hydrodynamics-based transfer of naked pDNA is a convenient and efficient method of IFN gene therapy against metastatic tumors.
Kobayashi
Naoki
N
Department of Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan.
Kuramoto
Takeshi
T
Chen
Shi
S
Watanabe
Yoshihiko
Y
Takakura
Yoshinobu
Y
D000818:Animals; D002455:Cell Division; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000473:pathology; D015316:Genetic Therapy; D007275:Injections, Intravenous; D016898:Interferon-alpha / Q000235:genetics* / Q000627:therapeutic use*; D016899:Interferon-beta / Q000235:genetics* / Q000627:therapeutic use*; D008113:Liver Neoplasms / Q000235:genetics / Q000556:secondary / Q000628:therapy; D008175:Lung Neoplasms / Q000235:genetics / Q000556:secondary / Q000628:therapy; D051379:Mice; D009362:Neoplasm Metastasis / Q000235:genetics* / Q000628:therapy*; D009368:Neoplasm Transplantation; D010957:Plasmids / Q000008:administration & dosage* / Q000235:genetics; D013997:Time Factors; D019076:Transgenes / Q000235:genetics
D016898:Interferon-alpha; D016899:Interferon-beta