IN-VIVO ANTITUMOR EFFECT OF RETROVIRUS-MEDIATED GENE-TRANSFER OF THE ADENOVIRUS E1A GENE

The adenovirus E1a gene has been shown to be associated with high sens itivity to DNA-damaging agents and a decrease in the tumorigenicity of some human malignant cell lines. We have analyzed the tumorigenicity of the murine epidermoid carcinoma cell lines MSC11A5 and HaCa4, which have constitutive E1a expression, after the concomitant injection of retrovirus E1a producer cells with the carcinoma cells and even after the intratumoral injection of the El a producer cells. The level of E1 a expression was studied by Western blotting. Tumors induced by carcin oma cell lines expressing Ela showed greater latencies and less tumori genicity. In the spindle cell carcinomas MSC11A5, El a gene expression partially blocked tumorigenicity. Similar results were obtained after the concomitant injection of the carcinoma cells and the retrovirus E l a producer cells. Intratumoral injection of retrovirus E1a producer cells was associated with a significant delay of tumorigenicity. By tr ansfection with different E1a mutants Ntd1598, d1922/947, and d1787N, we observed that only the mutant that has complete CR2 domains is asso ciated with the decrease in tumorigenicity. According to these results , we conclude that, at least in these carcinoma cell lines, Ela expres sion exerts a significant antitumor effect in vivo that is mediated by the CR2 region of E1a gene. We propose that injection of retrovirus E 1a producer cells may be a novel therapeutic approach in cancer.