Adenovirus-mediated p53 gene therapy for human cancer

Recent advances in molecular biology have fostered remarkable insights into the molecular basis of neoplasms. Considerable evidence has accumulated that among the mechanisms of human cancer development are overexpression of dominant oncogenes, expression of mutant oncogenes, or specific chromosomal deletions or mutations that induce inactivation of tumor-suppressor genes. This understanding of cancer pathogenesis suggests that restoration of the function of critical gene products could halt or reverse these abnormalities, thus having a therapeutic effect. The p53 tumor suppressor gene has been implicated in many inherited and sporadic forms of malignancies in humans. Preclinical experiments have demonstrated that restoration of wildtype p53 function in the cancer cell by gene transfer is sufficient to cause antitumor effects such as cell-cycle arrest and induction of apoptosis. This approach has entered clinical testing and provided intriguing information about the intratumoral administration of an adenovirus vector expressing the wildtype p53 gene in non-small-cell lung cancer. The clinical study has also provided evidence of the bystander phenomenon, which is important for potential clinical efficacy. This article reviews recent highlights in this rapidly evolving field: p53 gene therapy for human cancer.