Inhibition of tumor cell growth by p21WAF1 adenoviral gene transfer in lung cancer.
Gene replacement therapy is potentially a very powerful tool, targeting specific molecular mediators of cancer development and progression. p21WAF1 (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 proliferation. Using a replication-deficient recombinant adenovirus (AdV) ((rAd)-p21) as a p21 gene delivery system, we have evaluated the effect of p21 introduction in lung cancer cells in vitro as well as in vivo. In in 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 infection compared with untreated cells, suggesting that p21-induced growth inhibition was due to G0/G1 arrest. We also tested the therapeutic efficacy of rAd/p21 in an in vivo human NSCLC model in SCID mice. Tumor-bearing mice were established by subcutaneous injections of NCI-H460 cells and treated by repeated intratumoral injections of rAd/p21. Intratumoral delivery of rAd/p21 significantly suppressed tumor growth and prolonged survival in rAd/p21-treated mice. Our in vitro and in vivo results 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 cancer.
Joshi
U S
US
Department of Pathology, Wayne State University School of Medicine, Karmanos Cancer Institute and Harper Hospital, Detroit, Michigan 48201, USA.
Chen
Y Q
YQ
Kalemkerian
G P
GP
Adil
M R
MR
Kraut
M
M
Sarkar
F H
FH
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology / Q000628:therapy*; D002455:Cell Division / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics*; D005260:Female; D018014:Gene Transfer Techniques; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology / Q000628:therapy*; D051379:Mice; D016513:Mice, SCID; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins