TUMOR-CELLS EXPRESSING THE HERPES-SIMPLEX VIRUS THYMIDINE KINASE GENEIN THE TREATMENT OF WALKER-256 MENINGEAL NEOPLASIA IN RATS

A promising strategy in the treatment of neoplastic meningitis involve s the use of herpes simplex virus-thymidine kinase (HSV-tk)-modified c ells. In these experiments the authors used cells expressing HSV-tk to treat meningeal carcinomatosis in the rat Walker 256 model. Intrathec al injection of 2 X 10(5) Walker cells resulted in a median survival t ime of 15 days. Up to 80% of animals implanted with HSV-tk-modified Wa lker cells (Walker-tk+) and treated with ganciclovir showed long-term survival (120 days or more), whereas the remaining animals died from t umor growth between 37 and 44 days after implantation. Tumor cells fro m an animal in which the treatment failed were cultured in vitro and w ere shown to be still sensitive to ganciclovir. However, continuous, g anciclovir administration for 6 weeks rather than 2 weeks did not impr ove survival. Histopathological studies confirmed leptomeningeal infil tration in the untreated Walker or Walker-tk+ animals. Walker-tk+ cell s were mixed with Walker cells in 1:1, 10:1, or 50:1 ratios, respectiv ely, and implanted intrathecally; the animals were treated with gancic lovir. All groups of treated animals had long-term survivors, with 40% of the rats in the 10:1 and 50:1 groups demonstrating long-term survi val and absence of microscopic tumors in the brain or spinal cord. Sim ilarly, murine fibroblast HSV-tk virus-producer cells improved surviva l. Walker-tk+ cells were better than fibroblast-producer cells in impr oving the survival of animals with Walker tumors at low (1:1) but not at high (10:1) effector-to-target cell ratios. Repeated intrathecal ad ministration of Walker-tk+ cells resulted in inhibition of established Walker tumors. The authors conclude that Walker-tk+ cells are at leas t as effective as murine virus-producer cells and could be used in the treatment of meningeal neoplasia.