The prognosis for patients with recurrent malignant gliomas is poor. For patients with the common type of primary central nervous system malignancy, glioblastoma multiforme, most patients survive only 6-9 months from the time of diagnosis. Available surgical, radio therapeutic and chemotherapeutic options achieve at best transient responses in a minority of patients treated. Innovative therapeutic approaches to this tumor are clearly needed. Gene therapy characterized by direct introduction of therapeutic genes into malignant cells in vivo may provide an effective treatment of solid tumors including tumors of the central nervous system (CNS). This technique has shown promising results in numerous animal studies. Animal experiments indicate that this gene therapy strategy causes selective tumor cytotoxicity and spares the quiescent nonneoplastic and glial cells.
The aim of our phase I study is to determine the maximum dose of adenovirus vector carrying the herpes simplex thymidine kinase gene which can be safely administered with ganciclovir to patients after resection of recurrent malignant glioma. Patients that meet the entry criteria will receive an intraparenchymal injection of adenovirus carrying the herpes simplex virus thymidine kinase (HSV-tk) gene at the time of neurosurgical resection. Twenty-four hours after surgery, patients will be administered ganciclovir intravenously for 7 days. The tk enzyme phosphorylates the nucleoside analog ganciclovir (GCV) into a phosphorylated intermediate that is incorporated into newly-synthesized DNA of dividing cells. The incorporated analog hinders further DNA replication leading to cell death and tumor regression.
| Germano, Isabelle M; Fable, Jennifer; Gultekin, S Humayun et al. (2003) Adenovirus/herpes simplex-thymidine kinase/ganciclovir complex: preliminary results of a phase I trial in patients with recurrent malignant gliomas. J Neurooncol 65:279-89 |
