Purpose: Epidermal growth factor receptor (EGFR) is commonly overexpressed in lung cancer.Cetuximab is a chimeric mouse-human antibody targeted against EGFR. Compared with its inhibitory properties, its immunologic mechanisms have not been well studied. In this study, we investigated the antibody-dependent cellular cytotoxicity (ADCC) activity of cetuximab against lung cancer cell lines. Experimental Design: We studied the correlation between EGFR expression in lung cancer cell lines and the ADCC activity of cetuximab as well as the influence of interleukin-2 and chemotherapy on the ADCC activity. EGFR expression was measured by a quantitative flow cytometric analysis and immunohistochemistry. The ADCC activity was assessed by a 4-h 51 Cr release assay. Peripheral blood mononuclear cells, purified Tcells, natural killer (NK) cells, and monocytes from healthy donors or lung cancer patients were used as effector cells. Results: Fresh peripheral blood mononuclear cells exhibited cetuximab-mediated ADCC activity against lung cancer cell lines at a low concentration of cetuximab (0.25 Ag/mL). A logarithmic correlation was observed between the number of EGFRs and ADCC activity. Even low EGFR expression, which was weakly detectable by immunohistochemistry, was sufficient for maximum ADCC activity, and further increases in EGFR expression on the target cells had no further effect on the ADCC activity. In addition, ADCC activity was enhanced by interleukin-2 mainly through activation of NK cells and was less susceptible to immunosuppression by chemotherapy than NK activity in lung cancer patients. Conclusions: These observations suggest the importance of ADCC activity as an immunologic mechanism of cetuximab in biological therapy for lung cancer patients.
In patients with clinical stage IA non-small cell lung cancer (NSCLC), we investigated whether the maximum standardized uptake value (SUVmax) of 18F-fluorodeoxyglucose (FDG) by the tumor correlated with lymph node metastasis, intratumoral lymphatic and vascular invasion of tumor cells, and pleural invasion. From April 2005 to November 2008, 58 patients underwent a lobectomy with systematic hilar and mediastinal lymph node dissection for clinical stage IA NSCLC. All patients had integrated FDG-positron emission tomography (PET)/computed tomography (CT) performed in our center as part of the preoperative workup within one month of resection. The relationships between the SUVmax and pathologic results of lymph node metastasis, intratumoral lymphatic and vascular invasion of tumor cells, and pleural invasion were examined. Compared with tumors with an SUVmax < or = 2.0, tumors with an SUVmax>2.0 had more frequent lymph node metastasis, intratumoral lymphatic and vascular invasion of tumor cells and pleural invasion (all P<0.05). Our results suggest that in patients with clinical stage IA NSCLC, SUVmax is an important predictor of tumor invasiveness.
Abstract. Bronchial asthma is a chronic inflammatory disorder of the airways, in which inflammation causes bronchial hyper-responsiveness and flow limitation in the presence of various stimuli. Pulmonary function in asthmatic patients frequently deteriorates between midnight and early morning, which has suggested a role for chronotherapy. Although relationships between bronchial asthma and the function of clock genes remain unclear, some medications given for asthma such as glucocorticoids or β 2 -adrenoceptor agonists may influence clock genes in vivo. In our studies of clock gene mRNA expressions in human bronchial epithelial cells in vitro and peripheral blood cells in vivo, we demonstrated that glucocorticoid or β 2 -adrenoceptor agonist treatment strongly induced human Per1 mRNA expression both in vitro and in vivo. Human peripheral blood cells provide a useful indication of peripheral clock gene mRNA expression in vivo.
HCEn cells respond to HSV-1 infection by initiating antigen presentation-related inflammatory responses, and they may serve as antigen-presenting cells.
These results suggest that the micropapillary components are a manifestation of aggressive behavior, as shown by the frequent lymph node metastases and pleural invasion. Surgeons should search more carefully for metastases and conduct a closer follow-up on these patients when this feature is present with lung adenocarcinoma.
Epidermal growth factor receptor (EGFR) is commonly overexpressed in malignant pleural mesothelioma (MPM). Cetuximab is a chimeric mouse-human antibody targeted against EGFR and induces potent antibody-dependent cellular cytotoxicity (ADCC). The action of cetuximab against MPM cells has not been well studied. Therefore, in this study, we investigated the antitumor activity of cetuximab against MPM cell lines, particularly with respect to ADCC activity in vitro and in vivo. EGFR expression of MPM cells was measured by a quantitative flow cytometric analysis and immunohistochemistry. The effect of cetuximab on growth inhibition was assessed using a modified MTT assay. The ADCC activity was measured by a 4-h 51Cr release assay using fresh or IL-2-activated peripheral blood mononuclear cells. In vivo antitumor activity of cetuximab was evaluated using an orthotopic implantation mouse model. Cetuximab-mediated ADCC activity against MPM cells was observed at low concentration (0.25 mg/ml) and was enhanced by IL-2, whereas no direct effect on growth inhibition was detected. A logarithmic correlation was observed between the number of EGFRs on MPM cells and ADCC activity. Low EGFR expression on the MPM cells, which was weakly detectable by immunohistochemistry, was sufficient for maximum ADCC activity. In the mouse model, cetuximab treatment with or without IL-2 significantly inhibited intrathoracic tumor growth and prolonged their survival. Our study shows that cetuximab has potent anti-MPM activity both in vitro and in vivo, mainly through the immunologic mechanism of ADCC. Cetuximab has the potential to be used as a novel therapy for MPM patients.
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