Treatment of leptomeningeal metastases in a rat model using a recombinant adenovirus containing the HSV-tk gene

Abstract

The authors constructed recombinant adenoviral vectors to investigate their potential for gene therapy treatment of leptomeningeal metastases. Several human cell lines that were derived from tumors occurring as leptomeningeal metastases and that were infected in vitro with major late promoter recombinant adenovirus containing the luciferase (luc) gene (IG.Ad.MLP.luc) showed high levels of expression. When these human tumor cell lines were infected in vitro with recombinant adenovirus harboring the herpes simplex virus-thymidine kinase (HSV-tk) gene (IG.Ad.MLP.TK), they were highly sensitive to the killing effects of ganciclovir (GCV). Transduction efficiency of leptomeningeal tumor cells in vivo was assessed by injecting 9-L rat brain tumor cells into the cerebrospinal fluid of Fischer rats via the cisterna magna. After 3 days, recombinant adenovirus containing the lacZ reporter gene (IG.Ad.MLP.lacZ) was injected via the same route. Six days after tumor cell injection, expression of the reporter gene was observed in tumor cells along the total neural axis. Subsequently, rats with leptomeningeal metastases were treated 3 days after tumor cell injection with HSV-tk. Beginning on the next day, GCV was injected intraperitoneally for 10 days. The rats that developed neurological symptoms were killed immediately. The symptom-free latency of every rat was determined. The rats treated with HSV-tk and subsequent GCV had significantly longer (p < 0.01) symptom-free latency than all control groups. This study demonstrates the feasibility and efficacy of this therapeutic approach in a rat model. Clinically, it should be used in the palliative treatment of patients with leptomeningeal metastases.