ADENOVIRUS-MEDIATED P53 GENE-TRANSFER INHIBITS GROWTH OF HUMAN TUMOR-CELLS EXPRESSING MUTANT P53 PROTEIN

Human malignancies are often characterized by mutations of the p53 tum or suppressor gene. In a large proportion of cases, the mutation resul ts in production of an altered protein than can bind and inactivate th e wild-type gene product. This ''dominant-negative'' activity of mutan t p53 molecules may limit the utility oi p53 gene therapy of cancer. U sing replication-deficient recombinant adenoviruses (rAd-p53) as a p53 gene delivery system, we evaluated the effects of p53 reintroduction on a series of 45 human cell lines containing wild-type, mutated, or n o p53 protein. Results indicate a p53-specific, dose-dependent, and pr omoter-specific growth inhibition of a majority of p53-altered cell li nes that correlates with the degree of adenovirus transgene expression . Similar effects were not observed on cells containing wild-type p53. rAd-p53 inhibited the growth of cells expressing various mutant p53 p roteins including those characterized as ''dominant negative mutants,' ' and the antiproliferative effects were not abrogated by high levels of endogenous mutated p53 protein. In vivo, rAd-p53 also suppressed tu mor growth and increased survival of nude mice bearing tumors that exp ress mutant p53. These results support a role for p53 gene therapy of cancer, including malignancies harboring mutations in this tumor suppr essor gene.