Gemcitabine-induced programmed cell death (apoptosis) of human pancreatic carcinoma is determined by Bcl-2 content

Background: Gemcitabine is a new nucleoside analogue that produces a clinic al response in 30% of patients with unresectable pancreatic carcinoma. The cytotoxic effects of many chemotherapeutic agents occur through induction o f programmed cell death (apoptosis), which is controlled by the bcl-2 gene family. We determined whether induction of apoptosis by gemcitabine in panc reatic carcinoma is associated with cellular Bcl-2 content. Methods: Four pancreatic carcinoma cell lines (MIA-PaCa-2, AsPC-1, Panc-1, and Panc-48) were screened by Western blotting for Bcl-2 protein expression . Dose-response relationships for the cytotoxic effects of gemcitabine were determined using methylthiotetrazole assays, and induction of apoptosis wa s confirmed by fluorescence-activated cell sorting analysis. MIA-PaCa-2 cel ls transfected with human bcl-2 were also analyzed for gemcitabine-induced apoptosis. Results: Pancreatic cancer cell lines expressed varying amounts of Bcl-2, a nd the 50% lethal dose for gemcitabine-induced apoptosis was correlated wit h Bcl-2 content. Furthermore, Bcl-2 overexpression was associated with a si gnificant increase in the 50% lethal dose for gemcitabine-induced apoptosis . Conclusions: Cellular Eel-2 content was directly correlated with the cytoto xicity of gemcitabine in pancreatic carcinoma. Therefore, routine immunohis tochemical analyses may be useful in predicting gemcitabine efficacy, and p atients who would Likely not benefit could be spared gemcitabine administra tion. Furthermore, the effectiveness of gemcitabine and other chemotherapeu tic agents may be increased by gene therapy-mediated alteration of bcl-2 ge ne family members.