Immunoproteasome responds to injury in the retina and brain.

It is well known that immunoproteasome generates peptides for MHC Class I occupancy and recognition by cytotoxic T lymphocytes (CTL). The present study focused on evidence for alternative roles for immunoproteasome. Retina and brain were analyzed for expression of immunoproteasome subunits using immunohistochemistry and western blotting under normal conditions and after injury/stress induced by CTL attack on glia (brain) or neurons (retina). Normal retina expressed substantial levels of immunoproteasome in glia, neurons, and retinal pigment epithelium. The basal level of immunoproteasome in retina was two-fold higher than in brain; CTL-induced retinal injury further up-regulated immunoproteasome expression. Immunoproteasome up-regulation was also observed in injured brain and corresponded with expression in Purkinje cells, microglia, astrocytes, and oligodendrocytes. These results suggest that the normal environment of the retina is sufficiently challenging to require on-going expression of immunoproteasome. Further, immunoproteasome up-regulation with retinal and brain injury implies a role in neuronal protection and/or repair of damage.

Isolation and characterization of erlotinib-resistant human non-small cell lung cancer A549 cells.

Erlotinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is an effective therapy for non-small cell lung cancer (NSCLC). However, resistance to erlotinib reduces its efficacy. To investigate the basis of erlotinib resistance, we isolated erlotinib-resistant human NSCLC A549 cells, termed A549/ER cells. The A549/ER cells were found to be resistant to erlotinib, as well as paclitaxel and gemcitabine. We then performed a PCR array to investigate the resistance to erlotinib in A549/ER cells. EGFR expression in A549/ER cells was decreased compared to A549 cells. The expression of fibroblast growth factor 2 (FGF2) and p21 in A549/ER was increased when compared to A549 cells. Our results suggest that the down-regulation of EGFR and up-regulation of FGF2 is related to resistance to erlotinib in A549/ER cells.

Vorinostat: A novel therapy for the treatment of cutaneous T-cell lymphoma.

PURPOSE: The pharmacology, pharmacokinetics, clinical efficacy, safety, adverse effects, dosage and administration, and role in therapy of vorinostat in the treatment of cutaneous T-cell lymphoma (CTCL) are reviewed. SUMMARY: Vorinostat is a novel histone deacetylase (HDAC) inhibitor approved for the treatment of advanced CTCL. Its primary biochemical mechanism is to correct an aberrant balance between acetylated and deacetylated histones, the proteins involved in chromatin structure and organization. Vorinostat is metabolized and excreted following glucuronidation by the uridine diphosphate glucuronosyl-transferase (UGT) enzyme system. Polymorphisms in the gene encoding for this enzyme system, UGT1A1, may be an important predictor of vorinostat toxicity and response levels in individual patients. Vorinostat is not metabolized by and does not inhibit the cytochrome P-450 isoenzyme system, and only two drug interactions have been noted with vorinostat: warfarin and valproic acid or other HDAC inhibitors. In two Phase II studies, patients with CTCL treated with oral vorinostat demonstrated significant reductions in skin lesions and decreased disease progression. The overall response rate was approximately 30%, including one complete response and a time to response of approximately 10 weeks. At the approved 400-mg, once-daily dose, vorinostat was well tolerated, with the most common grade 1 or 2 adverse events being fatigue, nausea, and diarrhea. More-severe toxicities included thrombocytopenia, fatigue, and nausea and occurred in less than 6% of patients. CONCLUSION: Vorinostat, a novel HDAC inhibitor, is efficacious and well tolerated in patients with CTCL and is being investigated for its efficacy and safety in other types of cancers and as a part of combination therapy.