Ganciclovir mediated regression of rat brain tumors expressing the herpes simplex virus thymidine kinase imaged by magnetic resonance

Abstract

Using a rat C6 brain tumor model, we studied the antitumor effects of Herpes simplex virus type 1 thymidine kinase (HSV-tk) gene transfer followed by ganciclovir treatment. C6 glioma cells were transfected in vitro with the HSV-tk gene, and tested for their sensitivity to ganciclovir. Although there was no surviving cell at a 30 microM ganciclovir concentration, unmodified C6 cells were not affected by the drug. For in vivo experiments, intracerebral tumors were induced in rats by stereotactic injection of 10(4) HSV-tk-modified C6 cells. Ten days later, the animals were treated with intraperitoneal injections of ganciclovir for 21 days. The tumors evolution was evaluated by high resolution magnetic resonance imaging. In 33% of the rats, the signal intensity of the tumors became heterogeneous, with development of highly hyperintense areas, and a complete tumor regression was subsequently noted. Histological examination of successfully treated tumors revealed progressive necrosis with formation of cysts. The survival time of the HSV-tk/ganciclovir treated animals was consistently increased, all rats surviving more than 30 days and 33% of them being still alive after 80 days.

Rat Brain Tumor Models and the Statistical Evaluation of Survival Data in Experimental Neuro-Oncology

“…CCL-107). This tumor has been widely used in experimental neuro-oncology to evaluate the therapeutic efficacy of a variety of modalities, including chemotherapy (28,29), radiotherapy (30), immunotherapy (31), photodynamic therapy (32,33), and gene therapy (34)(35)(36)(37). The major limitation of this tumor is the fact that it arose in an outbred Wistar rat, and consequently there is no syngeneic host in which it can be used.…”

Evaluation of ganciclovir-mediated enhancement of the antitumoral effect in oncolytic, multimutated herpes simplex virus type 1 (G207) therapy of brain tumors

“…The use of herpes simplex virus thymidine kinase (HSVtk) gene transduction using replication-defective vectors followed by ganciclovir (GCV) administration is a therapeutic design that has been extensively studied in brain tumors. [3][4][5][6][7][8][9][10][11][12][13][14] GCV, a nucleoside analog, is phosphorylated by HSV-tk, but not by endogenous mammalian tk, and is further anabolized by cellular kinases to GCV triphosphate, which inhibits host cell DNA replication by chain termination. 15 An important, advantageous feature of this strategy is that surrounding nontransduced cells can be killed in the presence of GCV in addition to the cells transduced with HSV-tk gene.…”