Recent advances in experimental molecular therapeutics for malignant gliomas.

Abstract

The current lack of effective therapy for malignant gliomas has prompted the development of three primary foci of molecular research: anti-angiogenesis therapy, immunotherapy, and DNA- and RNA-based therapies. Angiogenesis inhibitors, designed to exploit the highly vascularized nature of gliomas, target endothelial cells and/or the extracellular matrix and bypass many of the problems of conventional chemotherapy. There may be easy access to the molecular target (e.g. blood vessels), reduced induction of drug resistance, and general lack of host toxicity. The relatively immunoprivileged status of the brain has also prompted use of immune stimulation as an anti-glioma strategy. Lines of attack include global cytokine therapy, vaccination with specific tumor antigens, dosing with monoclonal antibodies conjugated to radioisotopes or toxins, and ex vivo priming of lymphocytes. With regard to DNA- and RNA-based therapy, numerous oncogenic proteins have been targeted by antisense molecules administered alone or in combination with conventional chemotherapy and radiation. In one tactic, termed "suicide" gene therapy, herpes simplex thymidine kinase has been transfected into glioma cells via a retrovirus; subsequent introduction of ganciclovir causes cytotoxicity in the transduced cells. Although considerable preclinical data have been accumulated, promising results for therapy of human glioma have only recently appeared.