ABSTRACT
Global alterations in chromatin structure profoundly influence gene expression in thoracic neoplasms, silencing tumor suppressors while facilitating the expression of various cancer testis antigens such as NY-ESO-1. Although recent studies have shown that histone deacetylase inhibitors can potentiate tumor suppressor gene induction mediated by demethylating agents in cancer cells, the ability of these agents to augment cancer testis antigen expression have not been fully defined. The authors designed the current study to determine whether the histone deacetylase inhibitor, depsipeptide FR901228 (DP), could enhance NY-ESO-1 induction mediated by the DNA demethylating agent 5-Aza-2'-deoxycytidine (DAC) in cell lines established primarily from thoracic cancers. Quantitative reverse-transcriptase polymerase chain reaction analysis revealed that, under exposure conditions potentially achievable in clinical settings, DAC dramatically induced NY-ESO-1 expression in cultured cancer lines. DP alone mediated negligible target gene induction but significantly augmented DAC-mediated induction of NY-ESO-1. After DAC or sequential DAC-DP treatment, HLA-A*0201 cancer cells were recognized by an HLA-A*0201 CTL specific for NY-ESO-1. Although sequential DAC/DP exposure did not uniformly enhance immune recognition of target cells compared with DAC alone, this treatment mediated profound induction of apoptosis in cancer cells but not normal human bronchial epithelia. The apoptotic effects of DAC, DP, or sequential DAC-DP did not correlate in an obvious manner with histology, or the magnitude of NY-ESO-1 induction in cancer cells. Although the mechanisms have not been fully defined, sequential DAC-DP treatment may be a novel strategy to augment antitumor immunity in cancer patients.
Subject(s)
Anti-Bacterial Agents/therapeutic use , Antibiotics, Antineoplastic/therapeutic use , Apoptosis/drug effects , Depsipeptides , Membrane Proteins , Neoplasms/pathology , Peptides, Cyclic , Proteins/immunology , T-Lymphocytes, Cytotoxic/immunology , Anti-Bacterial Agents/pharmacology , Antibiotics, Antineoplastic/pharmacology , Antigens, Neoplasm/immunology , Blotting, Western , Breast Neoplasms , Carcinoma, Non-Small-Cell Lung , Carcinoma, Squamous Cell , Esophageal Neoplasms , Flow Cytometry , Humans , Lung Neoplasms , Melanoma , Mesothelioma , Neoplasms/drug therapy , Neoplasms/immunology , Pleural Neoplasms , Proteins/analysis , Tumor Cells, CulturedABSTRACT
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: Sequential DAC/DP treatment may be a novel strategy to simultaneously augment MAGE-3 expression and induce growth arrest in thoracic malignancies.
Subject(s)
Antigens, Neoplasm/metabolism , Azacitidine/analogs & derivatives , Depsipeptides , Esophageal Neoplasms/metabolism , Lung Neoplasms/metabolism , Neoplasm Proteins/metabolism , Peptides, Cyclic , Adenocarcinoma/metabolism , Anti-Bacterial Agents/pharmacology , Antibiotics, Antineoplastic/pharmacology , Azacitidine/pharmacology , Carcinoma, Non-Small-Cell Lung/metabolism , DNA Modification Methylases/antagonists & inhibitors , Decitabine , Enzyme Inhibitors/pharmacology , Histone Deacetylase Inhibitors , Humans , Immunohistochemistry , Melanoma/metabolism , Neoplasm Proteins/genetics , RNA, Messenger/analysis , Reverse Transcriptase Polymerase Chain Reaction , Tumor Cells, Cultured/drug effectsABSTRACT
Individual cases of crossed aphasia (aphasia after a right hemisphere lesion in a right-hander) have often been reported. A number of theories have been proposed as to the neuropsychological and/or nerobiological mechanisms that might underlie this phenomenon, but there is still disagreement about its language phenomenology and possible significance. We report 2 cases of crossed aphasia after stroke and review 34 cases from the literature with anatomical documentation of lesion site. Analysis of this material suggests that they represent at least two populations. There may be general conclusions concerning mechanisms of cerebral lateralization to be learned from the investigation of anomalous groups such as crossed aphasics.
