Biomedical subjects

D J McConkey

Publications and source records attributed to D J McConkey.

93 records · Page 6Linked to original sources

PubMedDate not supplied

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 clinical response in 30% of patients with unresectable pancreatic carcinoma. The cytotoxic effects of many chemotherapeutic agents occur through induction of programmed cell death (apoptosis), which is controlled by the bcl-2 gene family. We determined whether induction of apoptosis by gemcitabine in pancreatic 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 was confirmed by fluorescence-activated cell sorting analysis. MIA-PaCa-2 cells transfected with human bcl-2 were also analyzed for gemcitabine-induced apoptosis. RESULTS: Pancreatic cancer cell lines expressed varying amounts of Bcl-2, and the 50% lethal dose for gemcitabine-induced apoptosis was correlated with Bcl-2 content. Furthermore, Bcl-2 overexpression was associated with a significant increase in the 50% lethal dose for gemcitabine-induced apoptosis. CONCLUSIONS: Cellular Bcl-2 content was directly correlated with the cytotoxicity of gemcitabine in pancreatic carcinoma. Therefore, routine immunohistochemical analyses may be useful in predicting gemcitabine efficacy, and patients who would likely not benefit could be spared gemcitabine administration. Furthermore, the effectiveness of gemcitabine and other chemotherapeutic agents may be increased by gene therapy-mediated alteration of bcl-2 gene family members.

Adenocarcinoma↗

PubMedDate not supplied

Prognostic factors in resectable pancreatic cancer: p53 and bcl-2.

The p53 tumor suppressor gene and the Bcl-2 proto-oncogene regulate cell cycle progression and apoptosis. We evaluated the expression of these molecular markers with standard pathologic prognostic variables in patients who received multimodality therapy for resectable adenocarcinoma of the pancreas to study the effect of p53 and Bcl-2 on survival duration. Immunohistochemical staining of archival material was performed to determine levels of expression of p53 and Bcl-2 proteins in 70 patients with adenocarcinoma of pancreatic origin. All patients underwent a potentially curative pancreaticoduodenectomy and standardized pathologic analysis of resected specimens. Potential pathologic and molecular prognostic variables were assessed for their effect on survival duration. Nuclear staining for p53 was observed in 33 (47%) of 70 specimens. Immunostaining for Bcl-2 was observed in 23 specimens (33%). A trend toward improved survival duration was seen in patients whose tumors stained positive for either p53 or Bcl-2. Negative staining for both markers predicted short survival (P = 0.01). By univariate and multivariate analyses, no single pathologic factor was associated with survival duration. Immunohistochemical staging using both p53 and Bcl-2 significantly predicted survival duration by univariate and multivariate analysis; patients whose tumors stained positively for p53 and/or overexpressed Bcl-2 had a significantly longer survival than those whose tumors stained negative for both proteins.

Adenocarcinoma↗

PubMedDate not supplied

Caspase-dependent apoptosis induced by telomere cleavage and TRF2 loss.

Chromosomal abnormalities involving telomeric associations (TAs) often precede replicative senescence and abnormal chromosome configurations. We report here that telomere cleavage following exposure to proapoptotic agents is an early event in apoptosis. Exposure of human and murine cancer cells to a variety of pro-apoptotic stimuli (staurosporine, thapsigargin, anti-Fas antibody, and cancer chemotherapeutic agents) resulted in telomere cleavage and aggregation, and finally their extrusion from the nuclei. Telomere loss was associated with arrest of cells in G2/M phase and preceded DNA fragmentation. Telomere erosion and subsequent large-scale chromatin cleavage were inhibited by overexpression of the anti-apoptotic protein, bcl-2, and two peptide caspase inhibitors (BACMK and zVADfmk), indicating that both events are regulated by caspase activation. The results demonstrate that telomere cleavage is an early chromatin alteration detected in various cancer cell lines leading to drug-induced apoptosis, and suggest that this event contributes to mitotic catastrophe and induction of cell death. Results also suggest that the decrease of telomeric-repeat binding factor 2 (TRF2) may be the earliest event in the ara-C-induced telomere shortening, induction of endoreduplication and chromosomal fragmentation leading to cell death.

Animals↗