Background: The major emphasis on the safety of viral vectors for gene delivery has led to the generally accepted approach of disabling their ability to replicate and thus their potential capacity to spread throughout a tumor by consecutive rounds of infection and lysing neighboring cells.
Methods: In this study we evaluated three herpes simplex virus-1 thymidine kinase (HSV-tk) carrying replication-competent adenoviral vectors with and without the Ad5 E1B 55-kDa gene, wild-type adenovirus type 5 (Ad5wt), and a prototypical replication-deficient adenovirus expressing HSV-tk (Ad.TK) for their cytoreductive effects in a peritoneal carcinomatosis model from human HT-29 colon cancer cells in nude mice.
Results: The survival of nude mice treated with the replication-defective adenoviral vector Ad.TK was enhanced when followed by GCV. In contrast, administration of GCV diminished the anti-tumor efficacy of the replication-competent HSV-tk expressing vectors. However, the intrinsic oncolytic effect of all replication-competent viruses was superior to that of Ad.TK+GCV. Furthermore, the oncolysis of the E1B 55-kDa-positive viruses was significantly greater than that of the E1B 55-kDa-deleted vector.
Conclusions: The more efficient diffusion of viral particles in the peritoneal cavity, when compared to the microenvironment of solid tumors and the virostatic effects of GCV, most likely antagonized the anticipated enhanced cytotoxicity of the replication-competent vectors from the use of its gene directed enzyme prodrug system. Nevertheless, in a clinical setting, the HSV-tk/GCV system allows efficient termination of viral replication in the case of a runaway infection. The results of this study warrant further evaluation of controllable viral replication as a treatment modality for cancer, especially in combination with conventional therapies (e.g. chemotherapy).