Glucosamine induces activated T cell apoptosis through reduced T cell receptor.

Glucosamine (GlcN), like N-acetylglucosamine (GlcNAc), is salvaged into the hexosamine pathway and is converted to UDP-GlcNAc. Golgi N-glycan branching enzymes produce N-glycans, using UDP-GlcNAc as a substrate, which attach to the T cell receptor (TCR) and cytotoxic T-lymphocyte antigen-4 (CTLA-4). These findings suggest that GlcN exerts the immunoregulation through TCR signalling, which could be involved not only in cytokine production but also activated T cell apoptosis. In fact, a preliminary study showed that GlcN reduced the number of CD3+ T cells of NC/Nga mice with AD-like skin lesions. Therefore, whether apoptosis of T cells would be one of the potential molecular mechanisms of GlcN-induced immunosuppression was investigated. Cultured human primary along with Jurkat T cells and purified T cells from NC/Nga mice with or without Df-induced AD-like skin lesion were used for the study. Glucosamine treatment increased the number of T cells expressing ß1,6GlcNAc-branched N-glycans, with reduced ZAP-70 phosphorylation and enhanced CTLA-4 expression. Glucosamine treatment reduced the number of activated T cells from both the human primary and Jurkat cells and the dermatitis-induced mice. The expression of FasL and activated caspases, particularly caspase-3, was increased, whereas the phosphorylation of PI3K, Akt and NF-κB was decreased by GlcN treatment. Therefore, in addition to down-regulating TCR signalling and promoting CTLA-4 expression, GlcN may also suppress T cell function by enhancing apoptosis of activated T cells, through both extrinsic and intrinsic apoptotic signalling pathways, which were regulated by the inhibition of PI3K/Akt and NF-κB phosphorylation.

Therapeutic effects of combination using glucosamine plus tacrolimus (FK-506) on the development of atopic dermatitis-like skin lesions in NC/Nga mice.

Tacrolimus (FK-506) has been found to exhibit potent inhibitory effects on spontaneously developed dermatitis. We previously showed that glucosamine prevents the development of Atopic dermatitis (AD)-like skin lesions in NC/Nga mice. The aims of our study were to investigate the synergistic therapeutic efficacy of combination of glucosamine plus FK-506 in dermatophagoides farina (Df)-induced AD-like skin lesions in NC/Nga mice and to determine the underlying therapeutic mechanisms. The Df-induced NC/Nga mice with a clinical score of 8 were used for treatment with glucosamine (500 mg/kg) alone, FK-506 (1.0 mg/kg) or in combination. The synergistic effects of combination therapy were evaluated by dermatitis scores, skin histology and immunological parameters such as IgE, Th2-mediated cytokines and chemokines, CD3(+) T cells and CLA(+) T cells. Combined therapy using glucosamine plus FK-506 improved the development of AD-like skin lesions as exemplified by a significant decrease in total skin symptom severity scores. The suppression of dermatitis by combined therapy was accompanied by a decrease in the plasma level of IgE and in the splenic level of IL-5, IL-13, TARC and eotaxin. Histological finding indicated that the dermal infiltration of inflammatory cells including mast cells and eosinophils was greatly reduced. Particularly, immunohistological evaluation reveals a reduction in CD3(+) T cells and CLA(+) cells in the combined therapy. Our findings suggest that combination therapy of glucosamine plus FK-506 was more synergistic efficacy than single-modality treatment with either alone to improve the development of established dermatitis in NC/Nga mice model. This combined immunosuppressive therapy may provide an effective therapeutic strategy for the treatment of AD.

Glucosamine improved atopic dermatitis-like skin lesions in NC/Nga mice by inhibition of Th2 cell development.

Dysregulated Th subset responses, characterized by Th2-dominant allergic inflammation, are thought to be central to the pathogenesis of atopic dermatitis (AD). Glucosamine has been shown to have immunosuppressive properties, but its effect on AD has not been examined. In this study, the immunoregulatory effects of glucosamine, using dermatophagoides farinae (Df)-induced AD-like skin lesions in NC/Nga mice, were investigated. The clinical scores were reduced significantly by the treatment with glucosamine at 10 and 20 mg/day. Histological analysis of the skin also revealed that treatment of glucosamine at 10 and 20 mg/day significantly reduced the inflammatory cellular infiltrate, including mast cells and eosinophils. The levels of serum IgE and Th2 cytokines in spleen cells were reduced, whereas no significant change was detected in IFN-γ, a Th1 cytokine. To determine the mechanism associated with inhibition of the Th2 immune response, the effects of glucosamine on the selective differentiation pathway of the Th subset in vitro was examined in NC/Nga mice. The results showed that glucosamine suppressed the differentiation of naïve CD4(+) T cells to Th2 cells in vitro. On the basis of in vivo and in vitro results of the NC/Nga mice, the immunobiological effects of glucosamine on peripheral blood mononuclear cells from patients with AD were examined. The production of Th2 cytokines, such as IL-4 and IL-5, was significantly decreased after in vitro administration of glucosamine, which suggest that glucosamine might be a useful immunomodulatory agent for the treatment of human AD.

Adjuvant chemotherapy in non-small cell lung cancer.

Adjuvant chemotherapy is considered a standard of care for many malignancies, the most well known being breast and colon cancer. Unfortunately, less than a third of patients with non-small cell lung cancer (NSCLC) present with resectable disease and despite resection outcomes are often poor with a median 5-year survival of 40-50%. Modern chemotherapy for NSCLC provides both a survival advantage and an improvement in quality of life in the palliative setting. Several large studies using modern platinum-based regimens have been presented since the 1995 meta-analysis. This demonstrated a nonsignificant benefit for older platinum-based regiments. These studies have consistently shown a survival benefit across all stages of resection with acceptable toxicity. The absolute magnitude of benefit is consistent with that achieved in other malignancies where adjuvant chemotherapy is offered as a standard of care.

The management of PS2 patients with advanced non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths in the Western world. Patients with impaired performance status (PS2 or greater) have both worse prognosis and toxicity from treatment in general. The median survival of PS2 patients with advanced NSCLC is 4-5 months in comparison with the 8-9 months expected for those with good performance status (PS0-1). PS2 represents 30%-40% of all patients with advanced NSCLC, and their management remains controversial. In general, they have been excluded from most clinical trials. The emphasis on treatment should be on maintenance and improvement of quality of life with treatment strategies that provide rapid clinical improvement.

Gemcitabine and oxaliplatin followed by paclitaxel and carboplatin as first line therapy for patients with suboptimally debulked, advanced epithelial ovarian cancer. A phase II trial of sequential doublets. The GO-First Study.

OBJECTIVES: Gemcitabine and oxaliplatin are active in epithelial ovarian cancer with minimal overlapping toxicity. We studied the efficacy and toxicity of this combination in patients with advanced ovarian cancer when given prior to carboplatin and paclitaxel. METHODS: Chemonaive patients with epithelial ovarian cancer and measurable disease were eligible for the study. Treatment consisted of gemcitabine 1250 mg/m2 on days 1 and 8 and oxaliplatin 130 mg/m2 on day 8 every 21 days (GO) for 4 cycles. This was followed by carboplatin AUC = 6 and paclitaxel 175 mg/m2 on day 1 every 21 days (CP) for 4 cycles. RESULTS: Twenty patients, median age 62 years (range 39-78), FIGO stages III (16) and IV (4) received treatment. The response rate (RR) after 4 cycles of GO was 80% (95%CI 61-99%) (4 complete responses (CR), 12 partial responses (PR)). Interval debulking surgery was performed in 7 patients (35%). After CP chemotherapy, RR increased to 85% (95%CI 68-100%) (CR = 13, PR = 4). Median time to progression was 14.5 months. Estimated median overall survival was 31.5 months. Toxicities of GO were mild; grade 3/4 nausea in 3 patients (15%) and vomiting in 2 patients (10%), grade 3/4 neutropenia in 5 patients (25%). Grade 2/3 peripheral neuropathy occurred in 5 patients (25%). After sequential administration of CP, grade 2/3 neuropathy occurred in 13 patients (72%). CONCLUSION: The sequential doublet regimen of GO followed by CP resulted in unacceptable neurotoxicity and is not recommended for further study; however, the doublet gemcitabine and oxaliplatin has significant activity in the first line treatment of patients with ovarian cancer.

Management of the elderly patient with advanced non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is the most lethal of the common solid malignancies. It is predominantly a disease of the elderly with the median age at diagnosis 68 years. Unfortunately, the majority of patients present with advanced disease whereby palliation is the primary aim of treatment. The elderly have a long history of undertreatment and non-inclusion in clinical trials with regard to cancer. Elderly-specific studies demonstrate that chemotherapy provides both a survival and quality-of-life benefit in advanced NSCLC. Increasing emphasis is placed on the objective assessment of fitness for chemotherapy and the integration of molecularly targeted agents into treatment paradigms.