PROTEIN AND MESSENGER-RNA EXPRESSION OF CONNEXIN43 IN ASTROCYTOMAS - IMPLICATIONS IN BRAIN-TUMOR GENE-THERAPY

The expression of connexin43, the primary gap-junction constituent of glial cells, was evaluated at the messenger RNA and protein levels in different grades of astrocytoma to investigate the relevance of gap ju nctions in herpes simplex virus-thymidine kinase (HSV-tk)-mediated gen e therapy of brain tumors. Transduction of the retroviral-mediated HSV -tk gene into tumor cells with subsequent administration of ganciclovi r has recently been used as an experimental therapeutic strategy for t reatment of brain tumors. One aspect of this approach is the bystander effect, which augments the efficacy of this therapeutic approach. Gli oblastoma cells with minimum levels of connexin43 protein were transfe cted with a connexin43 complementary DNA. These cells manifested a mar ked increase in the in vitro bystander effect, supporting the contenti on that the ill vine bystander effect is a consequence of metabolic co operation between cells mediated by gap junctions. To assess relative levels of gap-junction protein expression in the relevant tumor type. we examined primary astrocytomas, primary astrocytoma cell cultures, a nd glioblastoma cell lines. Although most astrocytoma tumor samples ex pressed connexin43, they differed in the level of expression, with the greatest variation exhibited in high-grade astrocytomas. Primary glio blastoma cell cultures and established glioblastoma cell lines also di splayed some variability in connexin43 levels. In aggregate, our resul ts anticipate that glioblastomas will have a varied bystander effect d uring HSV-tk gene therapy depending on the level of connexin43 express ion.