Multimodal cancer treatment mediated by a replicating oncolytic virus thatdelivers the oxazaphosphorine/rat cytochrome P4502B1 and ganciclovir/herpes simplex virus thymidine kinase gene therapies

Multimodal therapy is generally more effective than single-agent treatment for cancer. rRp450 is an engineered herpes simplex viral mutant that replic ates in and kills tumor cells in a relatively selective fashion. It also ex presses, in infected cells, the cyclophosphamide (CPA)-sensitive rat cytoch rome P450 2B1 (CYP2B1) and the ganciclovir (GCV)-sensitive herpes simplex v irus thymidine kinase (HSV-TK) transgenes. We show that cultured rat 9L and human U87 Delta EGFR glioma cells, infected and lysed by rRp450, also exhi bit supra-additive sensitivity to both CPA and GCV, as determined by Chou-T alalay synergy analysis. DNA cross-linking, assayed by ethidium bromide flu orescence, was significantly inhibited in the presence of GCV, suggesting t hat interactions between the CPA/CYP2B1 and GCV/HSV-TK gene therapies occur red at the level of DNA repair. In vivo, regression of 9L s.c. tumor volume s in athymic mice was achieved only by the multimodal treatment allowed by rRp450 viral oncolysis combined with CPA/CYP2B1 and GCV/HSV-TK gene therapi es, whereas all other treatment combinations produced only tumor growth ret ardation.