Gene Therapy of Brain, Liver and Colon Malignancies Using Anti-Gene IGF-I Approach

Abstract

Aims: The oncoproteins, insulin-like growth factor type I (IGF-I) is present in normal fetal/neonatal development, absent from mature tissues, and it reappears in the development of malignant tumors. This study aims to evaluate the efficacy of targeting IGF-I in reducing brain tumor (glioblastoma), liver (hepatocarcinoma), and colon (adenocarcinoma) using a cancer gene therapy approach.

Background: IGF-I is involved in the development of all three embryonic derivatives but especially in normal and neoplastic neurogenesis and glial differentiation with a predominant role compared to other growth factors.

Methodology: When human tumor cells derived from brain glioblastoma, and comparatively studied primary hepatocarcinoma and colon adenocarcinoma are transfected in vitro with vectors expressing either IGF-I antisense RNA or inducing IGF RNA-DNA triple helix, the synthesis of IGF-I is stopped on translation or transcription levels, respectively (anti – gene strategy). Three cancer groups of two patients each, cancer stage I, after surgery and radiotherapy, were injected using anti–gene IGF-I transfected cells (’vaccines’). In the pilot clinical essay of glioblastoma treatment, the vaccines of anti-IGF-I/phytochemical type were applied.

Results: Down regulation in the expression of IGF-I coincides with the reappearance of B7 and MHC class I antigens at the surface of transfected cells (immunogenicity). When injected subcutaneously, the ‘vaccines’ initiate an immune reaction involving CD8+ lymphocytes, followed by tumor regression. The median survival of treated glioblastoma patients was 19 months, and even 21 months applying anti-gen/phytochemical vaccines (an average of 15 months, using chemotherapy). Using the same strategy, the patients with liver carcinoma and colon adenocarcinoma were comparatively treated; the obtained immune anti-tumor response mediated by TCD8 was like that of glioblastoma patients.

Conclusion: Cancer gene therapy (immuno-gene therapy of anti-gene IGF-I approach) constitutes one of the current efficient therapies for glioblastoma and other malignancies expressing IGF-I. The clinical observations should be considered as personal medicine treatment due to the personal preparation of vaccines, and moreover, the anti-gene therapy is associated with a marked personal tendency to increase CD8 immune anti-tumor response followed by an increase in median survival.