Adenovirus-mediated transfer of the p53 family genes, p73 and p51/p63 induces cell cycle arrest and apoptosis in colorectal cancer cell lines: potential application to gene therapy of colorectal cancer

p53 gene therapy is being tested clinically for the treatment of human canc er, however, some cancer models (in vivo and in vitro) are resistant to p53 . To explore the potential use of two p53 homologues, p73 and p51/p63, in c ancer gene therapy, we introduced p53, p73 and p51/p63 into colorectal canc er cell lines via adenoviral vectors, and compared their effects on cell gr owth. Among 10 cell lines tested, six cell lines displayed a similar respon se following transduction of p53, p73 beta or p51A/p63 gamma; two lines und erwent cell-cycle arrest, three lines exhibited apoptosis and one line show ed no-effect following transduction. The effect on cell-cycle progression w as variable in the other four cell lines. Interestingly, three cell lines w ere resistant to p53-mediated apoptosis, including two lines having endogen ous wild-type p53 alleles, but underwent apoptosis after transduction of p7 3 beta or p51A/p63 gamma. Similar to p53, transduction of p51A/p63 gamma in duced extensive apoptosis when combined with adriamycin or X-radiation in S W480 cells, which are normally resistant to apoptosis. Transduction of p73 beta and p51A/p63 gamma also reduced the tumorigenicity of two colorectal c ancer cells in vivo. These results suggest that adenovirus-mediated p73 bet a and p51A/p63 gamma transfer are potential novel approaches for the treatm ent of human cancers, particularly for tumors that are resistant to p53 gen e therapy.