TUMOR-SELECTIVE TRANSGENE EXPRESSION IN-VIVO MEDIATED BY AN E2F-RESPONSIVE ADENOVIRAL VECTOR

Recent data suggest that many tumors, such as malignant gliomas, have disrupted pRB function, either because of RB-1 gene mutations or as a result of mutations affecting upstream regulators of pRB such as cycli n D1 or pl6/INK4a/MTS1 (ref. 1-5). Tumor suppression by pRB has been l inked to its ability to repress E2F-responsive promoters such as the E 2F-1 promoter(6,7). Thus, a prediction, which has not yet been demonst rated experimentally in vivo, is that EaF-responsive promoters should be more active in tumor cells relative to normal cells because of an e xcess of ''free'' E2F and loss of pRB/E2F repressor complexes. We demo nstrate that adenoviral vectors that contain transgenes driven by the E2F-1 promoter can mediate tumor-selective gene expression in vivo, al lowing for eradication of established gliomas with significantly less normal tissue toxicity than seen with standard adenoviral vectors. Our data indicate that de-repression of the E2F-1 promoter occurs in canc er cells in vivo, a finding that can be exploited to design viral vect ors that mediate tumor-selective gene expression.