INHIBITION OF PANCREATIC TUMOR-CELL GROWTH IN CULTURE BY P21(WAF1) RECOMBINANT ADENOVIRUS

New innovations are needed for the treatment of pancreatic cancer, as current treatments do not offer significant improvements in overall su rvival. p21(WAF1) -a tumor suppressor gene-acts as a downstream effect or of p53 function and a mediates G1 cell cycle arrest by inhibiting c yclin-dependent kinases, which promote cell growth. p21 expression has also been shown to increase more than 20-fold in senescent cells in c ulture. The replication-defective recombinant adenoviral system (rAd), a major innovation in gene transfer technology, has recently been use d in gene therapy applications for various malignancies but not for pa ncreas cancer. In this study we used rAd-p21 in cell growth inhibition studies of pancreatic tumor cell lines in vitro to explore its potent ial as a prospective gene therapy for pancreatic adenocarcinoma. We st udied two pancreatic cell lines in culture, HPAC and Hs766T. HPAC reve aled higher endogenous levels of p21 gene expression at the protein an d RNA levels compared to Hs766T. p21 induction was tested using differ ent doses of rAd-p21 to establish an optimum dose for significant indu ction of p21 gene expression. Tumor cell growth in culture following r Ad-p21 infection was also analyzed in both cell lines. HPAC and Hs766T cell lines showed a significant dose-dependent increase in p21 protei n expression when infected with rAd-p21. Both cell lines showed signif icant growth arrest, but Hs766T showed less cell growth inhibition tha n HPAC cells. Flow cytometric cell cycle analysis of rAd-p21-infected cells showed a statistically significant increase in the number of cel ls in G0/G1 in HPAC cells. Similar results were also obtained in Hs766 T cells, however, the data were not statistically significant. In conc lusion, pancreatic tumor cell growth can be inhibited by rAd-p21 in vi tro, with significant numbers of tumor cells reverting from S to G0/G1 , Thus rAd-p21 may be effective as a candidate gene therapy for pancre atic cancer and should be further evaluated with in vivo studies.