REEXPRESSION OF P16(INK4A) IN MESOTHELIOMA CELLS RESULTS IN CELL-CYCLE ARREST, CELL-DEATH, TUMOR SUPPRESSION AND TUMOR-REGRESSION

Absence of expression of the p16(INK4a) gene product is commonly obser ved in mesothelioma tumors and cell lines, while wild-type pRB express ion is maintained. We have examined the biologic and potential therape utic role of re-expressing p16(INK4a) gene product in mesothelioma cel ls and tumors. Following transduction with a p16(INK4a) expressing ade novirus (Adp16), over-expression of p16(INK4a) in mesothelioma cells r esulted in cell cycle arrest, inhibition of pRB phosphorylation, dimin ished cell growth, and eventual death of the transduced cells. Express ion of p16(INK4a) protein was accompanied by decreased expression of p RB as detected by immunoblot and immunohistochemistry. Experiments in mesothelioma xenografts demonstrated inhibition of tumor formation, tu mor growth arrest and diminished tumor size and spread. p16(INK4a) gen e product expression was also demonstrated in intraperitoneal xenograf ts of human mesothelioma cells, These results demonstrate that p16(INK 4a) gene transfer may play a therapeutic role in the treatment of meso thelioma.