ANTITUMOR IMMUNITY IS INVOLVED IN THE THYMIDINE KINASE-MEDIATED KILLING OF TUMORS INDUCED BY ACTIVATED KI-RAS(G12V)

We have established a syngeneic mouse tumor model to test the efficacy of the drug-sensitizing enzyme thymidine kinase from herpes simplex v irus (HSVtk) in vivo. Activated mutant Ki-ras (G12V) is frequently fou nd in human colon cancer and adenocarcinomas of the lung and pancreas. We have transformed BALB/c-3T3 cells by stable transfection of a plas mid directing the expression of the mutant Ki-ras cDNA. To transfer th e HSVtk gene into tumor cells we used a Moloney murine leukemia virus (MoMLV)-based retroviral vector that carries the HSVtk gene. In this s tudy we show that the activity of HSV-TK inhibits tumor growth in immu ne-compromised nude mice following GCV treatment for up to 50 days but is not sufficient to completely eliminate all tumor cells in these mi ce as evidenced by the occurrence of tumors between 40 and 50 days aft er tumor cell implantation. By contrast, immune-competent BALB/c mice develop a long-lasting antitumor immunity in response to HSVtk transdu ction and GCV treatment, indicating that the immune system is importan t for the long-term tumor suppression in vivo. In the presence of GCV co-culturing of tumor cells with HSVtk transfected cells leads to the efficient killing of HSVtk negative tumor cells. While this retroviral vector independent HSV-TK/GCV-mediated bystander effect is not suffic ient to inhibit tumor formation in athymic animals it is very efficien t in immune-competent syngeneic mice. Taken together the data indicate that the antitumor activity of HSV-TK is enhanced by an intact immune system.