Gene therapy for head and neck cancer. Comparing the tumor suppressor gene p53 and a cell cycle regulator WAF1/CIP1 (p21).
OBJECTIVE
To compare the efficacy of the tumor suppressor gene wild-type p53 with that of cell-cycle regulator WAF1/CIP1 as single-agent gene therapy for squamous cell carcinoma of the head and neck. EXPERIMENTAL METHODS AND DESIGN: Recombinant cytomegalovirus-promoted adenoviruses containing the wild-type p53 or WAF1/CIP1 (p21) genes were transiently introduced into squamous cell carcinoma of the head and neck cell lines. Standard Western blot analysis was used to determine expression in these cells of the proteins encoded by these genes. A nude mouse xenograft model of squamous cell carcinoma of the head and neck was used to investigate the in vivo efficacy of the repeated gene therapy interventions.


RESULTS
Western blot analysis showed marked induction of the WAF1/CIP1 tumor suppressor gene product by both the p21 adenovirus and the wild-type p53 adenovirus (as a secondarily transcribed product). In vitro growth curves demonstrated that the wild-type p53 adenovirus significantly inhibited cell growth in these cell lines, whereas direct induction of the p21 gene product did not. Repeated infection with wild-type p53 adenovirus significantly reduced the size of established subcutaneous tumors, whereas infection with a replication-defective viral control did not.


CONCLUSIONS
Wild-type p53 adenovirus exhibits substantial in vitro and in vivo tumor suppressor activity in squamous cell carcinoma of the head and neck cell lines. This tumor suppression is not a function of the induced WAF1/CIP1 (p21) transcriptional product. Further studies are required to investigate the potential for induction of apoptosis by gene therapy.
Clayman
G L
GL
Department of Head and Neck Surgery, University of Texas M. D. Anderson Cancer Center, Houston, USA.
Liu
T J
TJ
Overholt
S M
SM
Mobley
S R
SR
Wang
M
M
Janot
F
F
Goepfert
H
H
D000260:Adenoviruses, Human / Q000235:genetics; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000628:therapy*; D002478:Cells, Cultured; D015967:Gene Expression Regulation, Viral; D016147:Genes, Tumor Suppressor; D016158:Genes, p53; D015316:Genetic Therapy; D006258:Head and Neck Neoplasms / Q000628:therapy*; D006801:Humans; D066298:In Vitro Techniques; D011995:Recombination, Genetic