Strategies for molecular intervention in esophageal cancers and their precursor lesions.
ABSTRACT Molecular analysis of malignant transformation in Barrett's epithelium provides insight into the temporal nature and significance of individual genetic events during multistep esophageal carcinogenesis. Potential targets for intervention in esophageal neoplasms include mutations involving retinoblastoma (Rb) and p53 tumor-suppressor pathways as well as tyrosine kinase cascades, which are known to promote cell cycle progression. Data from recent experiments provide the preclinical rationale for novel pharmacologic interventions in established esophageal cancers, and suggest strategies for chemoprevention in patients at risk for the development of these neoplasms.
SourceAvailable from: Zong Sheng Guo[Show abstract] [Hide abstract]
ABSTRACT: Although MAGE-3 has been detected in approximately 40% of lung and esophageal cancers, expression of this cancer testis antigen appears to be below the threshold for immune recognition in patients with these malignancies. The aim of this study was to determine if the demethylating agent, 5-Aza-2'-deoxycytidine (DAC) and if the histone deacetylase inhibitor Depsipeptide FR901228 (DP) could enhance MAGE-3 expression in lung and esophageal cancer cells. Eleven lung and esophageal cancer lines and cultured normal human bronchial epithelial (NHBE) cells were exposed to normal media (NM), DAC, DP, or combination DAC/DP at varying concentrations and exposure durations. MAGE-3 expression was evaluated by quantitative RT-PCR (TaqMan) and immunohistochemistry techniques. Trypan blue exclusion techniques were used to examine the proliferation of cancer cells after drug exposure. Relative to untreated controls, MAGE-3 expression was enhanced 32-fold (range 3.9 to 110) by DAC alone (0.1 micromol/L x 72 h), 2.1-fold (0.4 to 4.2) by DP alone (25 ng/mL x 6h), and 57-fold (4.6 to 209) by sequential DAC/DP exposure. Increased MAGE-3 mRNA copy numbers coincided with enhanced protein levels in these cells. MAGE-3 expression persisted after drug exposure. Flow cytometry confirmed the presence of functional HLA class I expression in these cells. Sequential DAC/DP treatment mediated pronounced growth inhibition in cancer cells but not NHBE. Sequential DAC/DP treatment may be a novel strategy to simultaneously augment MAGE-3 expression and induce growth arrest in thoracic malignancies.The Annals of Thoracic Surgery 02/2001; 71(1):295-301; discussion 301-2. DOI:10.1016/S0003-4975(00)02421-8 · 3.63 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: Yu-Xiao Yang – University of Pennsylvania, Philadelphia, USADrug Discovery Today Disease Mechanisms 12/2006; 3(4):447-456. DOI:10.1016/j.ddmec.2006.10.006
[Show abstract] [Hide abstract]
ABSTRACT: Barrett's esophagus is characterised by the presence of specialised intestinal metaplasia in the lower esophagus. Its importance is related primarily to its link with adenocarcinoma of the lower esophagus, often preceded by dysplastic changes. The incidence of this carcinoma has increased dramatically over the last few decades. Although modern treatments, particularly acid suppression with proton pump inhibitors, have been most useful in controlling the reflux symptoms associated with Barrett's esophagus, they have not reduced the incidence of adenocarcinoma of the esophagus. The same can be said about anti-reflux surgery. Surgical excision of Barrett's esophagus has been advocated when high-grade dysplasia is detected; this carries considerable morbidity and mortality, so alternative treatments are being developed. This update summarises recent information concerning newer treatments aimed at eradicating Barrett's esophagus. These vary from thermal coagulation (using electrocoagulation and heater probes) to lasers, photodynamic therapy and mechanical methods. Of these, photodynamic therapy using a porphyrin precursor (5-amino-laevulinic acid) seems to give the most consistent satisfactory results with a minimum of complications. However, persistence of some metaplastic cells beneath the neo-squamous layer remains a problem. Ongoing effective acid control (by medical or surgical therapy) is also essential to prevent recurrence of Barrett's esophagus. Future research is aimed at perfecting these methods. Ultimately, it may be possible to understand the molecular biology which could help to predict which patients are at greatest risk of developing dysplastic and carcinomatous changes.Biomedecine [?] Pharmacotherapy 09/2000; 54(7):362-7. DOI:10.1016/S0753-3322(01)80002-0 · 2.11 Impact Factor