Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oral glucosamine has anti-inflammatory activity in rodents, and anecdotal evidence suggests that it may be clinically useful in inflammatory bowel disorders. A possible explanation is that supplemental glucosamine increases production of heparan sulfate (HS) proteoglycans by the vascular endothelium, thereby improving the endothelium's barrier function. Extravasation of leukocytes and metastatic cancer cells requires degradation of HS. Heparin can inhibit neutrophil activation, adhesion, and chemotaxis, and--like glucosamine--has been reported effective for managing inflammatory bowel syndromes. Cytokine-mediated loss of endothelial HS may be a key factor in the coordinated inflammatory response. These considerations suggest that glucosamine may have clinical utility in a range of inflammatory disorders, and should be assessed with regard to its impact on cancer metastasis and peripheral ischemic disease. In inflammatory bowel disease, fish oil, ginkgolides, and enteric-coated 5-aminosalicylic acid may safely complement the efficacy of glucosamine.
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PMID:Vascular heparan sulfates may limit the ability of leukocytes to penetrate the endothelial barrier--implications for use of glucosamine in inflammatory disorders. 988 30

Intercellular adhesion molecule-1 (ICAM-1) plays an important role in cell to cell interactions. In malignant melanoma, ICAM-1 expression correlates with malignant behavior. We used monoclonal antibodies, anti-ICAM-1, anti-CD4+, anti-CD8+, and anti-CD11c+ to study the effect of interferon-alpha (IFN-alpha) on the expression of ICAM-1 by melanoma cells in regional metastases and its correlation to the occurrence of CD4+, CD8+, and CD11c+ cells close to tumor cells and in the tumor stroma. We also estimated the expression of ICAM-1 and regressive changes in malignant melanoma metastases, correlating the duration of treatment to these effects of IFN-alpha. Twenty-three IFN-alpha-treated and 10 untreated patients with regional metastatic malignant melanoma were studied. The duration of IFN-alpha treatment influenced the expression of ICAM-1. In metastases from patients treated for 1 week only, 1 of 5 showed high expression of ICAM-1 compared with 6 of 11 of those treated for 3 weeks (p = 0.01, chi-square test for trend comparing untreated patients and patients with various durations of IFN-alpha treatment). In IFN-alpha-treated patients with low expression of ICAM-1, none of 7 metastases showed CD4+ cells infiltrating close to tumor cells, in contrast to 6 of 10 metastases expressing high amounts of ICAM-1 (p = 0.03). Similarly, the expression of ICAM-1 was found to correlate with the occurrence of CD8+ cells close to the tumor cells (p = 0.04). We also showed a correlation between ICAM-1 expression and histologic evidence of tumor regression (p = 0.02).
J Interferon Cytokine Res 1999 Feb
PMID:Expression of ICAM-1 during IFN-alpha-based treatment of metastatic malignant melanoma: relation to tumor-infiltrating mononuclear cells and regressive tumor changes. 1009 Apr 2

An inverse correlation exists between expression of the inducible nitric oxide synthase (iNOS) gene and the ability of cloned K1735 murine melanoma cell lines to metastasize. We have analyzed the basis for the difference in iNOS induction by interferon-gamma (IFN-gamma) and lipopolysaccharide (LPS) in metastatic and non-metastatic K1735 cells. Nuclear run-on (NRO) assays revealed an upregulation of iNOS transcription on treatment with IFN-gamma plus LPS in nonmetastatic cells but not in a metastatic line. Transcription factors IFN regulatory factor 1 (IRF-1) and NF-kappaB were induced and functional in both metastatic and nonmetastatic K1735 lines treated with IFN-gamma plus LPS. Furthermore, a reporter construct driven by the wild-type iNOS promoter was transcriptionally activated in both nonmetastatic and metastatic cells. The iNOS-inducible phenotype was dominant in somatic cell hybrids generated by the fusion of nonmetastatic and metastatic cells, suggesting that no inhibitors of iNOS expression are present in metastatic cells. We conclude that the selective block in iNOS transcription in metastatic K1735 cells is likely due to an alteration in iNOS gene regulatory sequences. However, no such alteration was detected within the 1.7 kb iNOS promoter region in metastatic cells.
J Interferon Cytokine Res 1999 Apr
PMID:Transcriptional basis for the differences in inducible nitric oxide synthase (iNOS) expression between nonmetastatic and metastatic murine melanoma cell lines. 1033 91

Interleukin-12 (IL-12) is a potent immunoregulatory cytokine that exhibits antitumor activity in many experimental tumor models. In the present study, we investigated the ability of IL-15, a cytokine sharing many functions of IL-2, to modulate antitumor effectiveness of IL-12 against B16F10 melanoma in mice. In a model of locally growing tumor, intratumoral (i.t.) administration of IL-12, in three cycles of five consecutive daily injections (0.1 mug) followed by 2 days of rest, led to considerable delay of tumor development but no curative response was achieved. When combined with IL-12, subtherapeutic doses of IL-15 (0.4 mug) pontentiated the antitumor effects of IL-12 and induced complete tumor regressions in 50% of mice. Similar results were obtained in a model in which tumor-bearing mice were intravenously co-injected with melanoma cells to induce metastases. Combined administration of IL-12 and IL-15 yielded greater antitumor activity than injections of either cytokine alone and resulted in prolonged survival of mice bearing locally growing tumor and metastases. Studies of immunological parameters in mice treated with both IL-12 and IL-15 have shown enhanced NK activity (against YAC-1 cells) in the spleen and stimulation of both NK activity and specific anti-B16F10 cytotoxic effector cells in tumor-draining lymph nodes (LN). The strong antitumor effect of the IL-12 + IL-15 combination correlated with a high serum level of IFN-gamma in the treated mice. Moreover, increased expression of IL-15Ralpha was demonstrated in LN lymphocytes isolated from mice injected with IL-12. This result together with findings of other authors showing enhanced expression of IL-12 receptor by IL-15 [1] suggests that the augmentation of the antitumor effect during the course of IL-12/IL-15-based therapy could result from reciprocal upregulation of receptors by both cytokines and synergistic effects on IFN-gamma induction.
Eur Cytokine Netw 1999 Sep
PMID:Subtherapeutic doses of interleukin-15 augment the antitumor effect of interleukin-12 in a B16F10 melanoma model in mice. 1047 91

Transforming growth factor-beta (TGF-beta) and interleukin 10 (Il-10) are cytokines that have a strong immunosuppressive ability. Their secretion by tumor cells is able to suppress an immunological response against tumor. Both factors have been shown to enhance tumor growth in glioblastomas and carcinoma of the breast. We determined the expression pattern of TGF-beta and Il-10 in squamous cell carcinomas of the head and neck (HNSCC) and a possible association with tumor stage and their pre-treatment cytokine serum levels. Cytokine expression in primary tumors and metastases of 21 patients with HNSCC was investigated by immunohistochemistry. To assess the TGF-beta2 and Il-10 levels in tumor patients before therapy 49 serum specimens were analyzed by ELISA. TGF-beta2 was detected in 95% of all tumor tissues analyzed and Il-10 in 79% of all tumors. TGF-beta2 was localized in tumor cells and tumor borders, while Il-10 was preferentially found in peritumoral connective tissue. Metastasizing tumors showed elevated pretreatment serum levels for TGF-beta2 and Il-10. There was no correlation between TGF-beta2 and Il-10 expression in tumor tissue and pretreatment serum levels. Our data show that the majority of HNSCC analyzed express TGF-beta2 and Il-10. A correlation between pretherapy elevated cytokine serum levels and tumor grade was shown.
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PMID:[Cytokine expression of transforming growth factor-beta2 and interleukin-10 in squamous cell carcinomas of the head and neck. Comparison of tissue expression and serum levels]. 1055 Mar 71

Interleukin-18 (IL-18) is known to synergistically enhance murine natural killer (NK) cell activity in vitro when combined with either IL-12 or IL-2. However, it has also been demonstrated that simultaneous administration of IL-18 and IL-12 to mice induces extraordinarily large amounts of interferon-gamma (IFN-gamma) in the serum. In this study, we examined the effects of a combination of IL-18 and IL-2 on in vivo NK cell activation in parallel with the induction of toxicity. In contrast to the IL-18 and IL-12 combination, the combined administration of IL-18 and IL-2 to BALB/c mice for 3 days induced neither high levels of IFN-gamma production nor other visible side effects. When compared with treatment with IL-18 or IL-2 alone, the combined treatment resulted in a significant increase in the number of DX-5 (pan-NK cells marker)-positive cells in spleens and a marked enhancement of splenic NK activity, as determined by standard cytotoxicity assays. Enhanced splenic cytotoxicity generated in the mice treated with both IL-18 and IL-2 was also observed against syngeneic Colon 26 adenocarcinoma cells. Consistent with this in vitro observation, combined treatment produced a significantly stronger inhibitory effect on the pulmonary metastases following i.v. injection of Colon 26 tumor cells than treatment with either cytokine alone. These results suggest that IL-18 combined with IL-2 potentiates in vivo NK cell activity and contributes to inhibition of tumor metastasis without inducing significant toxicity.
J Interferon Cytokine Res 2000 Feb
PMID:Interleukin-18 in combination with IL-2 enhances natural killer cell activity without inducing large amounts of IFN-gamma in vivo. 1071 58

The purpose of this study was to evaluate the potential efficacy of alternating two outpatient regimens for the treatment of metastatic renal cell cancer. These regimens consisted of 4 weeks of recombinant interleukin 2 (rIL-2) plus IFN-alpha2B followed by 4 weeks of 5-fluorouracil plus IFN-alpha2B. Fifty patients meeting eligibility criteria of previous Cytokine Working Group studies were treated on an outpatient basis. Patients received s.c. rIL-2 (Proleukin; Chiron, Emeryville, CA) during weeks 1-4 of the 8-week regimen. During weeks 1 and 4, the dosage for rIL-2 was 10 MIU/m2 twice daily on days 3-5, and the dosage for IFN-alpha2B (Intron; Schering Plough, Kenilworth, NJ) was 6 MIU/m2 on day 1. During weeks 2 and 3, the dosage for rIL-2 was 5 MIU/m2 on days 1, 3, and 5, and the dosage for IFN-alpha2B was 6 MIU/m2 on days 1, 3, 5. During weeks 5-8, 5-fluorouracil (750 mg/m2) was administered once weekly by i.v. infusion, and IFN-alpha2B (9 MIU/mZ) was administered as a s.c. injection three times weekly. Throughout the treatment, an assessment of quality of life was made and a symptom-distress scale was evaluated. There were two patients with complete responses (CRs) and seven with partial responses (PRs) for an objective response rate of 18% (95% confidence interval, 10-25). The median response duration was 8 months (range, 3-51+ months). The CRs lasted 5 months and 51+ months and the PRs ranged from 3+ to 18 months. After completing at least one course of treatment, eight patients (three with PR, one with minor response, four with stable disease) became CRs after surgery for remaining metastatic disease. Six remain alive at 43+ to 53+ months, and 5 remain disease-free since surgery. The median survival of the study group is 17.5 months, with a maximal follow-up of 53+ months. The range in survival is 1-53+ months. Toxicity was primarily constitutional. and treatment modifications were designed to maintain toxicity at grade 2/3. The most common toxicities during treatment with IL-2/IFN were fatigue, nausea/vomiting, anorexia, skin reaction, diarrhea, fever, and liver enzyme elevations. One-third had central nervous system toxicity (headache, depression, insomnia). During 5FU/IFN treatment, 49 of 50 patients experienced grade 2/3 myelosuppression during course 1. Eight patients experienced grade 4 toxicities. In conclusion, the activity of this alternating regimen is similar to that of IL-2/IFN alone, given in 4-week cycles. The addition of 5FU/IFN failed to increase the efficacy and added new toxicity (myelosuppression). This report does not confirm the results previously reported for either alternating or simultaneous administration of these three agents. Because 5FU does not appear to add to the antitumor activity of IL-2-based therapy for renal cancer, current efforts are directed toward a Phase III randomized comparison of high-dose i.v. bolus inpatient IL-2 treatment versus treatment with outpatient s.c. injection of IL-2 plus IFN.
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PMID:Phase II trial of interleukin 2, interferon alpha, and 5-fluorouracil in metastatic renal cell cancer: a cytokine working group study. 1099 27

Interleukin-6 (IL-6) is a pleiotropic cytokine that has been shown to regulate immune defense mechanisms and hematopoiesis. In addition, IL-6 may also be involved in malignant transformation and tumor progression. A poor prognosis in patients with multiple myeloma, renal cell carcinoma, ovarian cancer, or prostate cancer has been associated consistently with elevated IL-6 serum levels. The aim of this study was, therefore, to assess IL-6 serum levels in 68 advanced gastrointestinal cancer patients and to correlate them with prognosis. IL-6 serum levels were found to be significantly elevated in cancer patients with respect to controls. Moreover, patients with disseminated cancer displayed significantly higher IL-6 serum levels than patients without apparent metastases. On univariate analysis, both overall survival (OS) and time to disease progression (TTP) were shown to be affected by IL-6 serum levels. However, multivariate analysis failed to demonstrate an independent prognostic significance for IL-6 serum levels while confirming the role of previously established variables, such as performance status, carcinoembryonic antigen (CEA) serum levels, and distant metastases. In conclusion, this study showed that IL-6 serum levels were elevated in advanced gastrointestinal cancer patients and correlated with both OS and TTP. However, they were shown not to be an independent prognostic factor.
J Interferon Cytokine Res 2001 Jan
PMID:Interleukin-6 serum level correlates with survival in advanced gastrointestinal cancer patients but is not an independent prognostic indicator. 1117 80

The in situ function of tumour-infiltrating leukocytes (TIL) in human colorectal adenocarcinoma (CRC) is unclear. Local cytokine expression probably regulates the anti-tumour immune response and tumour immune surveillance. We examined the distribution of mRNA for IFN-gamma, TNF-alpha, IL-10 and IL-4 in TIL, and tumour cells freshly isolated from 21 surgically removed primary CRC, using a semiquantitative RT-PCR. Lamina propria-infiltrating leukocytes (LPL) and epithelial cells from normal colon mucosa of 10 CRC patients served as negative controls. Median levels of IFN-gamma and TNF-alpha mRNA were higher in TIL than LPL (p = 0.0002 and 0.0001). IL-10 mRNA was generally observed in TIL and LPL, but no or very small amounts of IL-4 transcripts were detected in TIL and LPL. TNF-alpha and IL-10 mRNA were more abundant in colorectal tumour cells than in the normal epithelial cells (p = 0.0136 and 0.0036). The number of IFN-gamma transcripts in TIL correlated negatively (p = 0.039) and the number of TNF-alpha transcripts in tumour cells correlated positively with the Dukes' stages (p = 0.0147). Our results suggest that TIL are characterized by a type 1 (Th1/Tc1-like) pattern of cytokine expression and function as T cells (and macrophages) in the local, cell-mediated anti-tumour immune response in early stages of CRC. Changes in IFN-gamma and TNF-alpha mRNA in TIL and tumour cells could be related to tumour progress (e.g. by T cell anergy) or forming of metastases, respectively.
Eur Cytokine Netw 2001 Mar
PMID:Characterisation of cytokine mRNA expression in tumour-infiltrating mononuclear cells and tumour cells freshly isolated from human colorectal carcinomas. 1128 51

Cytokine therapy for patients with metastatic renal cancer is based on observations suggesting this neoplasm may be responsive to immunotherapy. Two cytokines, interferon-alpha (IFN-alpha) and interleukin 2 (IL-2) produce tumor regressions in 10% to 15% of patients with metastatic disease. Randomized trials demonstrate a modest survival advantage for patients treated with IFN-alpha. Combinations of IL-2 and IFN-alpha appear to be associated with improved response rates, but no demonstrable effect on survival. Additions of other cytokines (eg, GM-CSF) or chemotherapy to this combination has been investigated, but results do not suggest they enhance the outcome. Patient selection remains an important issue in this patient population. Individuals who are asymptomatic and have limited pulmonary or soft-tissue disease are most likely to benefit. The roles of immune dysregulation and the addition of novel cytostatic agents to these regimens are under investigation.
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PMID:Cytokine therapy for metastatic renal cell carcinoma. 1135 35


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