The prognosis of patients with malignant glioma, the most common primary brain tumor is grim despite contemporary surgery, radiation, and chemotherapy. New approaches for the treatment of brain tumors are urgent. The p53 tumor suppressor gene is one of th

Herpes simplex virus thymidine kinase (HS-tk) gene transfer and gancyclovir (GCV) administration has been suggested for the treatment of malignant glioma. In order to understand tissue responses and possible ways to improve the treatment effect we studied tumor sizes and tissue reactions after HSV-tk/GCV treatment effect in a syngeneic BT4C rat glioma model. HSV-tk expressing BT4C glioma cells were mixed 0%, 1%, 30% and 100% with wild type BT4C glioma cells, followed by injection into BD IX rat brains (n = 36). Animals, which received HSV-tk expressing cells, were treated with GCV. No or very little astroglia or microglia reactivity were detected around the wild type tumors as analyzed by immunocytochemistry using GFAP-, HLA-DR-, Vimentin and CD68-specific monoclonal antibodies. After 10 d GCV treatment, 10% HSV-tk-positive cells produced a significant reduction in the tumor size (p < 0.05). Strong GFAP and Vimentin immunoreactivity were seen within the tumor scar area. GFAP and Vimentin immunoreactivity was already present in the group which received only 1% HSV-tk positive cells. No or very few CD68-positive cells were seen in the treated animals. Our results suggest that ≥10% transfection efficiency is required for a successful reduction in the BT4C glioma tumor size with HSV-tk/GCV treatment. Tissue reactions after 10 d GCV treatment is characterized by astrogliosis, as measured by GFAP and Vimentin immunoreactivity. On the other hand, very few CD68 positive cells were seen in the area. Improvement of the latter response by gene transfer or other means should enhance the efficacy of the HSV-tk/GCV treatment.