Considerable progress has been made recently in our understanding of the role of ceramide in the induction of apoptotic cell death. Ceramide is produced by cancer cells in response to exposure to radiation and most chemotherapeutics and is an intracellular second messenger that activates enzymes, leading to apoptosis. Because of its central role in apoptosis, pharmacologic manipulation of intracellular ceramide levels should result in attenuation or enhancement of drug resistance. This may be achieved through direct application of sphingolipids or by the inhibition/activation of the enzymes that either produce or use ceramide. In addition, attention should be given to the subcellular location of ceramide generation, because this has been shown to affect the biological activity of sphingolipids. This review summarizes the sphingolipid biosynthetic pathway, as it relates to the identification of important targets for drug discovery, and the development of novel agents capable of enhancing chemotherapy. [Mol Cancer Ther 2006;5(2):200 -8]

At a cutoff of 10.2 units/mL, 41 (77%) of 53 pancreatic cancer patients, none of the healthy individuals (n = 43), and only four (5%) of 87 patients with pancreatitis were positive above this value. Among nonpancreatic cancers investigated, colorectal cancers gave the highest percentage of positives (14%; five of 36). Overall, the sensitivity and specificity of the immunoassay for pancreatic cancer were 77% and 95%, respectively. Receiver operator characteristic analyses for discrimination of pancreatic cancer from pancreatitis provided an area under the curve of 0.89 (95% CI, 0.82 to 0.93), with a specificity of 95.4% and a positive likelihood ratio of 16.8. A direct pair-wise comparison of PAM4 and CA19-9 immunoassays for discrimination of pancreatic cancer and pancreatitis resulted in a significant difference (P < .003), with the PAM4 immunoassay demonstrating superior sensitivity and specificity. CONCLUSION The high sensitivity and specificity observed suggest that the PAM4-based immunoassay of circulating MUC1 may be useful in the diagnosis of pancreatic cancer.

Purpose: The anti-MUC1monoclonal antibody (MAb), PAM4, has a high specificity for pancreatic adenocarcinoma compared with other cancers, normal tissues, or pancreatitis. In order to assess its role in early pancreatic cancer development, we examined the expression of the PAM4-reactive MUC1 in the noninvasive precursor lesions, pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasia (IPMN). Most patients with pancreatic cancer do not develop symptoms until after the disease has metastasized. The early detection and diagnosis of pancreatic cancer, as well as appropriate staging of the disease, would almost certainly provide a survival advantage. With few options currently available, there remains a critical need for the development of procedures for the accurate detection of early pancreatic cancer. A growing body of evidence supports the view that pancreatic adenocarcinoma can arise from histologically well-defined noninvasive lesions within the pancreatic ducts (1 -3). These precursor lesions include pancreatic intraepithelial neoplasias (PanIN), and the larger intraductal papillary mucinous neoplasms (IPMN) and mucinous cystic neoplasms (3). These precursors are true neoplasms that share many of the aberrant genetic alterations and expression of biomarkers characteristic of invasive adenocarcinoma (4 -8). It has been proposed that PanIN lesions progress from the early PanIN-1A (flat epithelium with minimal atypia) and PanIN-1B (papillary epithelium with minimal atypia) to PanIN-2 (papillary epithelium with moderate atypia) to PanIN-3 (papillary epithelium with marked atypia), and eventually invasive adenocarcinomas.In an effort to improve the early detection of pancreatic neoplasia, several investigators have examined PanIN lesions for specific genetic and protein biomarkers. These include survivin (9), Her2neu (10, 11), mesothelin (2), p53 (2), DPC4 (2, 12), and several mucin species (MUC1, MUC4, MUC5AC, etc. refs. 2,6,(13)(14)(15) among others. For the most part, detection of these biomarkers has been shown by the use of immunohistochemical labeling of tissues. Certain biomarkers (e.g., mucins) are highly complex molecules that may, or may not, display specific epitope structures at varying stages in the progression from PanIN-1 to invasive adenocarcinoma. Indeed, discrepancies are apparent when MUC1 is identified by the use of monoclonal antibodies (MAb) that react with the variable number of tandem repeats (VNTR) core peptide versus MAbs reactive with glycosylated structures. MUC1 may be reported as present or absent from normal tissues, precursor lesions, and/or adenocarcinoma based on the specific MAb being used. Thus, caution is needed in determining which events (i.e., expression