P16(INK4A) ADENOVIRUS-MEDIATED GENE-THERAPY FOR HUMAN HEAD AND NECK SQUAMOUS-CELL CANCER

Inactivation of the tumor suppressor gene p16(INK4A) is the most commo n genetic alteration in human head and neck squamous cell cancer (HNSC C), making it an ideal target for gene replacement. We constructed a r eplication defective, recombinant adenovirus capable of directing a hi gh level of p16(INK4A) protein expression (Ad5-p16) to investigate its benefit in treating HNSCC, Initial in vitro experiments in four human HNSCC cell lines demonstrated that Ad5-p16 treatment significantly in hibits cell growth with up to 96% efficiency. Flow cytometric analysis showed that Ad5-p16 induced a maximum G(1)-S cell cycle arrest of 90% . Subsequent studies in a nude mouse model demonstrated that Ad5-p16 t reatment significantly reduced (cell line 011) or stabilized (cell lin e 012) established tumors when compared with control treatments (P < 0 .008), These results demonstrate for the first time a significant anti tumor effect of Ad5-p16 against human HNSCC in vivo and support the po tential application of Ad5-p16 to treat locally advanced, unresectable , or metastatic head and neck cancer, as well as microscopic residual disease after surgical resection.