Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0242379 (lung cancer)
 71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Idiopathic thrombocytopenic purpura (ITP)-like syndrome is a rare complication of carcinomas, and its treatment usually precedes cancer therapy in order to make further procedures safe. We describe the case of a 78-year-old man with a small-cell lung cancer of extended stage, associated with ITP-like syndrome, which proved resistant to treatment with corticosteroids and vincristine, short-responsive to IV immunoglobulin, but quickly and steadily responsive to low-dose interferon (ld IFN, 3 million IU, sc, twice weekly, for 8 weeks), until the patient's death, due to his primarily chemoresistant cancer. This case is, to our knowledge, the second reported ITP-like syndrome in a cancer patient who had been successfully treated with ld IFN. The excellent and cost-effective therapeutic index of ld IFN makes it an attractive alternative treatment in patients with this specific complication and calls for further investigation regarding its potential use as a first-line treatment.
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PMID:Successful treatment of idiopathic thrombocytopenic purpura-like syndrome in a cancer patient with low-dose interferon: case report and review of the literature. 1528 68

The objective of the study was to evaluate the number of myeloid (DC1) and lymphoid (DC2) dendritic cells in malignant pleural effusion and peripheral blood of patients with lung cancer as well as to estimate changes in their presence during intrapleural interferon alpha treatment. The study comprised eight subjects including two patients treated with Roferon A. Isolated mononuclear cells were phenotyped with the following monoclonal antibodies: anti-BDCA-1 FITC and anti-BDCA-2 FITC, and analyzed using FACSCalibur flow cytometry. Very low percentage of DC2 and high BDCA-1/BDCA-2 ratio in malignant pleural effusion of patients not treated with IFN-alpha suggest intensive Th1 response probably responsible for inflammatory state maintenance and effusion constant development. The results of our study indicate that apart from the suggested antitumour activity, IFN-alpha therapy may result in unfavourable immunotolerance caused by increased DC2 activity.
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PMID:Presence of dendritic cells in malignant pleural effusion: pilot study. 1531 85

5,6-Dimethylxanthenone-4-acetic acid (DMXAA) is a small molecule in the flavanoid class that has antitumor activity thought to be due to ability to induce high local levels of tumor necrosis factor (TNF)-alpha that disrupt established blood vessels within tumors. The drug has completed phase 1 testing in humans and is currently in phase 2 trials in combination with chemotherapy. Although characterized as a "vascular disrupting agent," there are some studies suggesting that DMXAA also has effects on the immune system that are important for its efficacy. The goal of this study was to carefully define the immune effects of DMXAA in a series of murine lung cancer and mesothelioma cell lines with varying immunologic characteristics. We show that DMXAA efficiently activated tumor-associated macrophages to release a variety of immunostimulatory cytokines and chemokines, including TNF-alpha; IFN-inducible protein-10; interleukin-6; macrophage inflammatory protein-2; monocyte chemotactic protein-1; and regulated on activation, normal T-cell expressed, and secreted. DMXAA treatment was highly effective in both small and large flank tumors. Animals cured of tumors by DMXAA generated a systemic memory response and were resistant to tumor cell rechallenge. DMXAA treatment led to initial tumor infiltration with macrophages that was followed by an influx of CD8(+) T cells. These CD8(+) T cells were required for antitumor efficacy because tumor inhibitory activity was lost in nude mice, mice depleted of CD8(+) T cells, and perforin knockout mice, but not in CD4(+) T-cell-depleted mice. These data show that activation of tumor-associated macrophages by DMXAA is an efficient way to generate a CD8(+) T-cell-dependent antitumor immune response even in animals with relatively nonimmunogenic tumors. Given these properties, DMXAA might also be useful in boosting other forms of immunotherapy.
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PMID:Activation of tumor-associated macrophages by the vascular disrupting agent 5,6-dimethylxanthenone-4-acetic acid induces an effective CD8+ T-cell-mediated antitumor immune response in murine models of lung cancer and mesothelioma. 1635 88

Dendritic cells (DC) resident in draining lymph nodes (LN) of patients with lung cancer are proposed to have a critical role in stimulating anti-tumor immunity. CpG oligodeoxynucleotides are undergoing clinical trials in patients with lung cancer and are likely to target plasmacytoid-DC. The present study, therefore, investigated the capacity of plasmacytoid-DC from human lung cancer draining LN to respond to CpG for activation of T cell responses relevant to anti-tumor immunity. The phenotype of DC was examined by flow cytometry, and cytokine production by cytometric bead array (CBA) and ELISA. Plasmacytoid-DC, purified by cell sorting, were immature but expressed the toll-like receptor, TLR9. Plasmacytoid-DC responded to the CpG oligodeoxynucleotide, CpG 2216, by production of the proinflammatory cytokines, IFN-alpha and IL-6. DC were cocultured with normal, allogeneic T cells, and cytokine production determined by CBA and immunophenotyping. CpG 2216 enhanced IFN-gamma production and induced intracellular production of IFN-gamma by CD8(+) and CD4(+), granzyme B by CD8(+), and IL-2 by CD4(+) T cells, respectively. Ligation of CD40 on plasmacytoid-DC combined with exposure to CpG 2216 also strongly enhanced IFN-gamma production. There was no significant difference between the responses of plasmacytoid-DC from patients with lung cancer and patients with benign carcinoid tumors with no pathologic LN involvement. These results indicate that plasmacytoid DC from the draining LN of patients with lung cancer effectively induce Tc1 immunity and could, therefore, represent a novel and attractive target for immunotherapeutic intervention.
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PMID:Plasmacytoid dendritic cells from human lung cancer draining lymph nodes induce Tc1 responses. 1702 87

Sixty-one non-small cell lung cancer (NSCLC) patients with stage II and III/IV were enrolled and 49 completed immunotherapy. Patients were grouped based on immunosuppressive acidic protein (IAP). All patients received monthly intravenous infusions containing 1 x 10(10) (mean cell number per patient) ex vivo expanded and IFN-alpha-treated peripheral blood mononuclear cells. No patients had grade 2 or greater adverse events. The patients with < or = 580microg/ml of serum IAP levels (n=33) had significantly longer recurrence-free survival than those with > 580microg/ml of serum IAP levels (n=16). Patients with lower IAP levels are still under immunotherapeutic control after 27 months free of recurrence. The IAP levels may be a prognostic marker for treatment efficacy in NSCLC. This immunotherapeutic regimen was feasible and well tolerated in patients with advanced NSCLC in terms of prolongation of survival.
Lung Cancer 2008 May
PMID:Cell transfer regimens in patients with highly advanced surgically unresectable non-small cell lung cancer: significantly improved overall survival in patients with lower levels of serum immunosuppressive acidic protein. 1798 Apr 54

Hyperthermia is used as one of the treatment modalities for various types of cancer, but the acquisition of thermotolerance in cancer cells, through the induction of heat shock proteins (Hsps), renders hyperthermia less effective. Among the Hsp family members, Hsp27 is frequently associated with thermotolerance and chemoresistance. Thus, down-regulation of Hsp27 expression during hyperthermic or chemotherapeutic applications is a promising approach to efficient tumor treatment. In the present study, we found that the cytokine interferon-gamma (IFN-gamma) suppresses the basal, the heat shock-induced and the cisplatin-induced expression of Hsp27 in HSC-2 (oral squamous carcinoma) and A549 (lung cancer) cells but not in 16HBE14o- (normal bronchial epithelial cells). Neither IFN-alpha nor IFN-beta affected Hsp27 expression, suggesting the specificity of IFN-gamma. We also demonstrate here that IFN-gamma suppresses Hsp27 basal transcription and promoter activity, and this is mediated specifically through one of the two Sp1 sites in the proximal region of the Hsp27 promoter. More importantly, pre-treatment of cells with IFN-gamma enhanced the induction of cell death by hyperthermia and cisplatin treatments in the tumor cell lines, HSC-2 and A549, but has no effect in 16HBE14o-, indicating a tumor cell-specific effect of IFN-gamma. Furthermore, the combination treatment of hyperthermia and IFN-gamma suppressed tumor growth in vivo more effectively than hyperthermia treatment alone. Together, our findings propose that IFN-gamma could be a useful potentiator of hyperthermia and cisplatin in cancer therapy.
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PMID:IFN-gamma down-regulates Hsp27 and enhances hyperthermia-induced tumor cell death in vitro and tumor suppression in vivo. 1849 94

CpG-oligonucleotides (CpG-ODN), which induce signaling through Toll-like receptor 9 (TLR9), are currently under investigation as adjuvants in therapy against infections and cancer. However, whether the CpG-ODN alone could enhance the anti-tumor immunity and the underlying mechanisms remains unclear. Here, we investigated that stimulation of peripheral blood mononuclear cells (PBMCs) from human lung cancer patients with CpG-ODN induced proliferation responses of the PBMCs, accompanied by the elevated cytokine secretion, including IFN-alpha, IL-12 and TNF-alpha. In addition, after treatment with CpG-ODN, the cytotoxic activity of the PBMCs and the production of IFN-gamma in CD8(+) T cells were dramatically enhanced. Furthermore, we found that adoptive transfer of CpG-ODN treated PBMCs significantly inhibited the tumor progression in nude mice, which were challenged with the autologuous tumor cells from human lung cancer patients. Finally, we demonstrated that the inhibitory CpG ODN or chloroquine could dramatically abrogate the enhanced anti-tumor responses of the CpG ODN treated PBMCs. Our findings suggest that the CpG-ODN is promising as a preventive and therapeutic anti-tumor measure against pulmonary carcinoma.
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PMID:Targeting toll-like receptor 9 with CpG oligodeoxynucleotides enhances anti-tumor responses of peripheral blood mononuclear cells from human lung cancer patients. 1856 66

We evaluated the therapeutic potential of the replication competent vector VA7-EGFP, which is based on the avirulent Semliki Forest virus (SFV) strain A7 (74) carrying the EGFP marker gene in an orthotopic lung cancer tumor model in nude mice. We have previously shown that this oncolytic vector destroys tumor cells efficiently in vitro and in vivo (in subcutaneous tumor model). Tumor growth in animals with orthotopically implanted adenocarcinoma cells (A549) were monitored during the study with small animal CT. We show that locally administered virotherapy with VA7-EGFP increased survival rate in experimental lung cancer significantly (p < 0.001) comparable to results obtained with the second generation conditionally replicating adenoviral vector Ad5-Delta24TK-GFP, used for comparison. The limited efficacy in systemically administered oncolytic viruses is the essential problem in oncolytic virotherapy and also in this study we were not able to elicit significant response with systemic administration route. Despite the fact that tumor microenvironment in orthotopic lung cancer is more optimal, viruses failed to home to the tumors and were unable to initiate efficient intratumoral replication. Clearly, the efficacy of virotherapy is influenced by many factors such as the route of virus administration, immunological and physiological barriers and cancer cell-specific features (IFN-responsiveness).
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PMID:Replication competent Semliki Forest virus prolongs survival in experimental lung cancer. 1865 70

UBE1L is the E1-like ubiquitin-activating enzyme for the IFN-stimulated gene, 15-kDa protein (ISG15). The UBE1L-ISG15 pathway was proposed previously to target lung carcinogenesis by inhibiting cyclin D1 expression. This study extends prior work by reporting that UBE1L promotes a complex between ISG15 and cyclin D1 and inhibited cyclin D1 but not other G1 cyclins. Transfection of the UBE1L-ISG15 deconjugase, ubiquitin-specific protein 18 (UBP43), antagonized UBE1L-dependent inhibition of cyclin D1 and ISG15-cyclin D1 conjugation. A lysine-less cyclin D1 species was resistant to these effects. UBE1L transfection reduced cyclin D1 protein but not mRNA expression. Cycloheximide treatment augmented this cyclin D1 protein instability. UBE1L knockdown increased cyclin D1 protein. UBE1L was independently retrovirally transduced into human bronchial epithelial and lung cancer cells. This reduced cyclin D1 expression and clonal cell growth. Treatment with the retinoid X receptor agonist bexarotene induced UBE1L and reduced cyclin D1 immunoblot expression. A proof-of-principle bexarotene clinical trial was independently examined for UBE1L, ISG15, cyclin D1, and Ki-67 immunohistochemical expression profiles in pretreatment versus post-treatment tumor biopsies. Increased UBE1L with reduced cyclin D1 and Ki-67 expression occurred in human lung cancer when a therapeutic bexarotene intratumoral level was achieved. Thus, a mechanism for UBE1L-mediated growth suppression was found by UBE1L-ISG15 preferentially inhibiting cyclin D1. Molecular therapeutic implications are discussed.
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PMID:UBE1L causes lung cancer growth suppression by targeting cyclin D1. 1907 53

Targeted therapy to the epidermal growth factor receptor (EGFR) seems to be related to its expression level on tumor cells. Interferon-alpha (IFN-alpha) induces growth inhibition but also may up-regulate the EGFR expression in some cancer cell lines. We aimed to determine whether the IFN-alpha combined with an EGFR-specific monoclonal antibody (nimotuzumab) may affect the growth of human tumor epithelial cell lines with different EGFR expression levels. H125, a lung adenosquamous carcinoma, and A431, a vulvar epidermoid carcinoma, cell lines express intermediate and high levels of EGFR, respectively, whereas MDA MB231, a breast adenocarcinoma cell line expresses undetectable levels of EGFR measured by flow cytometry/FACS. We found that IFN-alpha alone inhibited in a dose-dependent fashion the growth of all cell lines, but only up-regulated the EGFR expression in the lung carcinoma-derived cell line. Noteworthy, the combined treatment did not modify the complement-mediated cytotoxicity of the antibody although the antiproliferative activity of nimotuzumab in H125 cells in vitro increased when an IFN-alpha-conditioning treatment was used. In conclusion, this study may provide insights about the rational use of EGFR inhibitors into the immunopharmacological management of targeted therapies including the IFN-alpha for lung cancer.
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PMID:Interferon-alpha conditioned sensitivity to an anti-epidermal growth factor receptor monoclonal antibody in a human lung cancer cell line with intermediate expression of the receptor. 1951 42


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