The most common genetic alteration in human cancer involves the p53 tumor suppressor gene resulting in defective control of cell cycle arrest and cell death.
The p53 protein induces a cyclin-dependent kinase (cdk) inhibitor, p21 which occupies a central position in cell cycle regulation. Cdk inhibition by p21 results in dephosphorylation of retinoablastoma (Rb) and the inhibition of transcription factors that regulate many genes involved in DNA replication and cell-cycle progression. The effect of p21 on the cell cycle thus results in inhibition of progression from the G1 to the S-phase of DNA replication, and of progression through the G2 phase. P21 function is necessary for p53-mediated G1 arrest and overexpression of p21 results in an effective suppression of tumor growth in vitro and in vivo.
Since cells lacking the p53 tumor suppressor gene can also lack p21 functionality, it is hypothesized that the re-introduction of p53 or p21 into tumor cells will inhibit proliferation and regenerate the pathway to apoptosis (programmed cell death).
In our laboratory, we have demonstrated that an Antennapedia- p21 fusion protein can be used to transport the tumor suppressor protein p21 into neoplastic cells.
Our data show that in vivo, intra-venous administration of the fusion protein to tumor-bearing mice, induced cell-cycle arrest, inhibited tumor growth and prolonged survival. Furthermore, co-administration of the fusion protein with conventional chemotherapeutic agents resulted in enhanced growth inhibitory effects, tumor eradication and increased overall survival.