Adenovirus-mediated transfer of p53 and p16(INK4a) results in pancreatic cancer regression in vitro and in vivo

Pancreatic cancer has a very poor prognosis. Current chemotherapy and radio therapy regimens are only moderately successful. The tumour suppressor gene s p53 and p16(INK4a) encode cell cycle regulatory proteins that are importa nt candidates for gene replacement therapy. Over 80% of pancreatic adenocar cinoma cases lack detectable p16 protein while over 60% contain mutated p53 protein. We used replication-deficient recombinant adenoviruses to reintro duce wild-type p16 and p53 into pancreatic cancer cells in vitro and into s ubcutaneous pancreatic tumours in an animal model to determine the effect o n tumour growth. Significant growth inhibition was observed in all five hum an pancreatic cell lines with these viruses (P < 0.002) compared with simil ar control viruses expressing either luciferase or <beta>-galactosidase. G1 arrest was observed in all cell lines 72 h after infection with Adp16. Inf ection with Adp53 caused significant levels of apoptosis (P < 0.004). Apopt osis was also observed to a lesser degree (P < 0.03) with the Adp16 vector. Subcutaneous pancreatic tumours, generated in nu-nu mice demonstrated sign ificant growth suppression following injection of Adp53, Adp16 and a combin ation of both Adp53 and Adp16 (P < 0.0001). These results show that transfe r of wild-type p53 and p16 produces significant growth suppression of pancr eatic cancer in vitro and in vivo.