RESUMO
A recombinant adenovirus expressing human interferon alpha2b driven by the cytomegalovirus promoter, IACB, was shown to produce and secrete biologically active protein in vitro and in vivo. Intravenous administration of IACB in Buffalo rats resulted in circulating levels of biologically active human interferon at 70,000 international units/mL for up to 15 days. Distribution of interferon protein after IACB administration was different from that seen with the subcutaneous delivery of interferon protein. Higher levels of interferon protein were observed in liver and spleen after IACB delivery compared to protein delivery. The antitumor efficacy of IACB, as measured by suppression of tumor growth, was tested in athymic nude mice bearing established human tumor xenografts from different types of human cancer. Subcutaneous tumors most responsive to the intratumoral administration of IACB ranked as U87MG (glioblastoma) and K562 (chronic myelogenous leukemia), followed by Hep 3B (hepatocellular carcinoma) and LN229 cells (glioblastoma). Intravenous administration of IACB in animals bearing U87MG or Hep 3B xenografts was also effective in suppressing tumor growth, although to a lesser extent than the intratumoral administration. IACB was also tested in a metastatic model in beige/SCID mice generated with H69 (small cell lung carcinoma) cells and was found to prolong survival in tumor-bearing animals. This suggested that interferon gene delivery can be effective in suppressing tumor growth in a wide variety of cells.
Assuntos
Adenoviridae/genética , Terapia Genética/métodos , Vetores Genéticos , Interferon-alfa/genética , Neoplasias Experimentais/terapia , Animais , Western Blotting , Divisão Celular , Citomegalovirus/genética , Primers do DNA/química , Feminino , Humanos , Interferon alfa-2 , Interferon-alfa/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos ICR , Camundongos Nus , Camundongos SCID , Metástase Neoplásica , Neoplasias Experimentais/mortalidade , Proteínas Recombinantes , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Taxa de Sobrevida , Transplante Heterólogo , Células Tumorais CultivadasRESUMO
Interferons exhibit strong antiproliferative, antiviral and immunomodulatory properties. A combination of these properties makes them ideal candidates for the treatment of cancer and viral infections. However, their use as a protein therapeutic is limited due to their short serum half-life and certain undesirable side-effects. Some of these limitations are likely to be overcome by using interferons in a gene therapy modality. Gene therapy offers the advantage of generating higher sustained local concentration of this cytokine. In addition, it is possible to target the desired tissues and/or tumors by using specific promoters and to modulate the levels of the cytokine by using regulatable promoters. Results from studies in experimental tumor models of gene therapy for cancer and for certain viral infections have been encouraging and suggest that this may be a feasible and attractive alternative to interferon protein therapy.