ADENOVIRUS-MEDIATED HERPES-SIMPLEX VIRUS THYMIDINE KINASE GENE AND GANCICLOVIR THERAPY LEADS TO SYSTEMIC ACTIVITY AGAINST SPONTANEOUS AND INDUCED METASTASIS IN AN ORTHOTOPIC MOUSE MODEL OF PROSTATE-CANCER

It is critical to develop new therapies, such as gene therapy, which c an impact on both local and metastatic prostate cancer progression. We have developed an orthotopic mouse model of metastatic prostate cance r using a cell line (RM-1) derived from the mouse prostate reconstitut ion (MPR) model system. This mouse model closely simulates the anatomi cal and biological milieu of the prostate and allows for realistic tes ting of experimental gene therapy protocols. Adenovirus (ADV)-mediated transduction of the herpes simplex virus thymidine kinase (HSV-tk) ge ne in conjunction with ganciclovir (GCV) in this model led to signific ant suppression of growth and of spontaneous metastasis at 14 days pos t-tumor inoculation. Longer-term studies produced a significant surviv al advantage and a continued suppression of metastatic activity for tr eatment animals despite regrowth of the primary tumor. Challenge by in jection of tumor cells into the tail vein following excision of treate d and control s.c. primary tumors resulted in 40% reduction in lung co lonization in the treatment group, indicating the possible production of systemic anti-metastatic activity following a single in situ treatm ent with ADV/HSV-tk + GCV in this model system. (C) 1997 Wiley-Liss, I nc.