RESUMO
BACKGROUND: Death receptor 4 (DR4) and death receptor 5 (DR5) are tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) receptors that activate apoptosis via the extrinsic apoptosis pathway. DcR1 and DcR2 are decoy receptors for TRAIL that act antagonistically. Intracellular trafficking of TRAIL receptors has been described, but the role of the subcellular localization of TRAIL receptors in non-small cell lung cancer (NSCLC) progression is unclear. METHODS: Expression and intracellular localization of pro-apoptotic and decoy TRAIL receptors were analyzed by immunohistochemistry in 50 samples of advanced or recurrent NSCLC. Using confocal microscopy, localization of TRAIL receptors was studied in NSCLC cell lines. RESULTS: Cytoplasmic staining for all four TRAIL receptors was observed in the majority of samples. Nuclear staining was infrequent in the case of DR4 (12%) and DcR2 (8%), while DR5 and DcR1 were localized in the nucleus in 27% and 60% of samples. When overall survival was analyzed, cytoplasmic staining for DR5 in tumor cells (P=0.025) and nuclear staining for DR5 in tumor cells (P=0.007) were significant prognostic factors in univariate, as well as in multivariate analysis including clinicopathologic factors (P=0.026 and 0.021, respectively). In A549, NCI-H358, and A427 NSCLC cells all four TRAIL receptors were found to be mainly located perinuclearly, but also in the nucleus. CONCLUSION: The study for the first time shows that TRAIL receptors are found in different intracellular compartments including the nucleus in NSCLC cells and that both nuclear and cytoplasmic DR5 might predict improved survival in patients with advanced NSCLC.
Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Receptores do Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Adulto , Idoso , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Núcleo Celular/metabolismo , Citoplasma/metabolismo , Humanos , Neoplasias Pulmonares/patologia , Masculino , Microscopia Confocal , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Frações Subcelulares/metabolismoRESUMO
BACKGROUND: Palonosetron is a new generation 5-HT3-receptor antagonist with a significantly prolonged half-life and a once-a-day administration compared to the conventional setrons. To evaluate the antiemetic efficacy of palonosetron in the daily hospital practice setting, a postmarketing study was carried out in Austria. METHODS: Palonosetron was administered at 0.25 mg on day 1 of each cycle to 135 cancer patients who received moderately or highly emetogenic chemotherapy either as an IV bolus or as a short-term infusion. Two thirds of these patients were females (n = 90), the majority had breast cancer (n = 38) and the majority received cisplatin, carboplatin, anthracyclines, 5-fluorouracil or cyclophosphamide. RESULTS: The complete antiemetic response rate was 68 % overall with 87 % efficacy on day 1 and 72 % efficacy on days 2 to 5. Higher antiemetic response was achieved in male patients, in patients being aged > or = 50 years, and in chemonaive patients. Twenty-four percent of patients needed rescue medication. Only 1.5 % of patients reported mild adverse events. CONCLUSIONS: Palonosetron resulted in high antiemetic efficacy in this study. Female gender and age < or = 50 years should be particularly considered when the antiemetic regimen is selected.