INHIBITION OF TUMOR-CELL GROWTH BY P21(WAF1) ADENOVIRAL GENE-TRANSFERIN LUNG-CANCER

Gene replacement therapy is potentially a very powerful tool, targetin g specific molecular mediators of cancer development and progression. p21(WAF1) (p21) is a cyclin-dependent kinase inhibitor that is induced by p53 upon DNA damage or p53 overexpression, resulting in cell cycle arrest at the G1 checkpoint and inhibition of further cell proliferat ion. Using a replication-deficient recombinant adenovirus (AdV) ((rAd) -p21) as a p21 gene delivery system, we have evaluated the effect of p 21 introduction in lung cancer cells in vitro as well as in vivo. In i n vitro experiments, two human non-small cell lung cancer (NSCLC) cell lines, NCI-H460 and NCI-H322, showed dose-dependent p21 induction and concomitant cell growth inhibition following rAd/p21 infection. Flow cytometric analysis of the cell cycle revealed a significant increase in the percentage of NCI-H460 cells in G0/G1 following rAd/p21 infecti on compared with untreated cells, suggesting that p21-induced growth i nhibition was due to G0/G1 arrest. We also tested the therapeutic effi cacy of rAd/p21 in an in vivo human NSCLC model in SCID mice. Tumor-be aring mice were established by subcutaneous injections of NCI-H460 cel ls and treated by repeated intratumoral injections of rAd/p21. Intratu moral delivery of rAd/p21 significantly suppressed tumor growth and pr olonged survival in rAd/p21-treated mice. Our in vitro and in vivo res ults provide strong preliminary evidence for the growth inhibition of NSCLC by rAd/p21. Collectively, these results justify further studies to evaluate the efficacy of rAd/p21 for gene therapy in human lung can cer.