Applied physiology of IGF-I: case reports of gene therapy of malignant tumors especially glioma

Abstract

Abstract Introduction: Certain specific antigens, which behave as oncoproteins, are present in normal fetal/neonatal brain development, and are absent from mature brain tissues: among them, growth factors, especially insulin-like growth factor type I (IGF-I). When IGF-I reappears in the mature brain, this growth factor is over expressed in neoplastic glia, participating in the development of the most common human brain malignant tumor, glioblastoma multiforme, which is invariably fatal. Targeting the IGF-I system has emerged as a useful method to reduce glial malignant development. Methodology: In practice, in case-control study, when human glioblastoma cells, and comparatively studied primary hepatocarcinoma and colon adenocarcinoma cells derived from cancer biopsy, 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 antisense / triple helix ‘’vaccines’’ of 1 million irradiated cells. The control groups received injected placebo. 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 transfected cancer cells, “vaccines”, initiate an immune reaction involving CD8+ lymphocytes, followed by tumor regression. The glioblastoma patients treated by classical surgery and radiotherapy, were “vaccinated” by three successive injections. The median survival of treated patients was 21 months (current progress in treatment of this disease involves an increase in medium survival from 8-11 months to an average of 15 months, using a 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 similar to that of glioblastoma patients. Conclusion: The cellular immunogene therapy using anti - gene approach constitutes one of the current efficient therapies of glioblastoma and other malignancies expressing IGF-I. The described methodology applied in Europe, and previously in the USA for glioblastoma treatment, is introduced now in university hospitals of Colombia (Bogota).