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)

The hepatic sinusoidal endothelium (HSE) releases large amounts of reactive oxygen species (ROS) in response to endotoxins and interleukin-1 (IL-1). Such pro-inflammatory mediators have been shown to promote hepatic metastasis. We have investigated the involvement of ROS released by IL-1-stimulated HSE in this promoting effect. Recombinant human interleukin-1 beta (rHuIL-1 beta) (5 micrograms/kg) was intravenously injected into C57BL/6J mice, and the hepatic metastasizing ability of B16 melanoma cells following intrasplenic injection was studied in the presence of ROS scavengers. rHuIL-1 beta-promoted hepatic metastases were significantly (P < .01) reduced by catalase (1 mg/kg) and enhanced by recombinant human superoxide dismutase (rHuSOD) (5 mg/kg). rHuIL-1 beta-stimulated HSE-conditioned medium (HSE-CM) significantly (P < .01) enhanced B16 melanoma cell adhesion to HSE compared with unstimulated HSE-CM, which in turn also significantly (P < .01) increased with melanoma cell adherence compared with basal medium. The addition of catalase completely abrogated proadhesive effects induced by rHuIL-1 beta-stimulated HSE-CM with respect to unstimulated HSE-CM, but did not affect the proadhesive effects induced by unstimulated HSE-CM over basal medium. The rat monoclonal antibody to mouse vascular cell adhesion molecule-1 (VCAM-1) significantly (P < .01) inhibited the enhanced melanoma cell adherence effects of both unstimulated and rHuIL-1 beta-stimulated HSE-CM, indicating that adherence was very late antigen-4 (VLA-4)-mediated. Not surprisingly, the percentage of VLA-4 expressing B16 melanoma cells significantly (P < .05) increased in response to unstimulated (21% of controls) and rHuIL-1 beta-stimulated (32% of controls) HSE-CM. Catalase addition abrogated these effects of rHuIL-1 beta-stimulated-HSE-CM. Melanoma cell damage was observed from the second hour of adhesion to HSE and significantly (P < .01) increased when the cells adhered to rHuIL-1 beta-stimulated HSE. This increase was abrogated by catalase. Cytolysis of the HSE was not observed during melanoma cell adhesion. Neither was the enhancement of B16 melanoma hydrogen peroxide production observed in response to rHuIL-1 beta. Thus, the effects of IL-1 in the liver may consist of a balance between the prometastatic effect of enhanced adherence to the HSE and the antimetastatic effect of H2O2-mediated cytotoxicity. Our results suggest that the enhancement of H2O2 production by the rHuIL-1 beta-stimulated HSE may contribute to the hepatic metastasis progression of ROS-resistant melanoma cells. Results in vitro indicate that this progression is associated with a H2O2-mediated increase in melanoma cell adhesion to HSE.
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PMID:Sinusoidal endothelium release of hydrogen peroxide enhances very late antigen-4-mediated melanoma cell adherence and tumor cytotoxicity during interleukin-1 promotion of hepatic melanoma metastasis in mice. 909 86

Platelets and coagulation are involved in the pathogenesis of blood-borne metastases. The aim of this study is to obtain more information about the mechanisms involved in the initial adhesion of tumor cells to endothelial cells. In short term experiments with tumor cells, suspended in the medium of cultured endothelial cells, we tested whether addition of both platelets and thrombin cause more tumor cell adhesion to endothelial cells, than when either platelets or thrombin are acting alone. HeLa cells or HT29 cells, prelabeled with radioactive 51Cr, human platelets, and thrombin were added to human endothelial cell cultures. Following 15 min of shaking at 37 degrees C, the percentage of tumor cell adhesion was calculated. The percentages of adhering tumor cells with the presence of both platelets and thrombin were greatly increased compared to controls. Addition of hirudin 2 min before thrombin lowered the adhesion percentage of tumor cells. Hirudin added immediately before and 2 min after thrombin gave only minor effects. When the endothelium was treated with superoxide dismutase, catalase, and mannitol, the adhesion of tumor cells was lowered with catalase and superoxide dismutase. The cause of tumor cell-endothelial cell interaction is probably complex. Our results show that activated platelets enhance the tumor cell adhesion, and that generation of active oxygen species may be important in the initial phase of the interaction.
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PMID:Addition of both platelets and thrombin in combination accelerates tumor cells to adhere to endothelial cells in vitro. 911 26

During the last 15 years 2404 radical operations of various types were carried out for cancer of the rectum. The rate of postoperative complications made up 28.3% and mortality--2.9%. The tendency to increase of locally spread forms of cancer up to 96.2% with metastases to regional lymph nodes up to--52.3% was detected. The use of adequate chemotherapy, updated suturing devices and new variants of radical operations, combined and extended ones in particular havw much contributed to carrying out radical interventions with complete restoration of bowel continuity in 70% of patients. 5 year survival rate of patients after sphincter saving plastics and restorative procedures made up 60.2-65.3%, after extirpations with colostomy--54.2%. Promising results of improvement the indices of 5 year survival were obtained when preoperative irradiation in regime of multifractioning SOD 45-55 Gy was used together with administration of 5-fluorouracil (5-7.5 g).
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PMID:[Up-to-date approach to the treatment of rectal cancer]. 979 92

Metastasis is a complicated multi-step process involving interactions between tumour cells, the extracellular matrix and the vessel walls. Experimental observations suggest that leucocyte migration and function could be a suitable model in order to understand tumour cell dissemination. In the present report we show and quantify the production of free radicals by human malignant melanoma cells (St-ml12) by means of a spectrophotometrical method, using an enzyme immunoassay reader. Endothelial cells and activated polymorphonuclear leucocytes were used as controls. Melanoma cells without stimulants produced large amounts of superoxide anion at an increasing rate in relation to time, which could be inhibited by superoxide dismutase. Production of hydrogen peroxide was minimal. The endothelial cells produced a negligible amount, in contrast to the activated polymorphonuclear leucocytes, which released large quantities of both free radicals. A rapid assay to analyse the production of free radicals by tumour cells is presented here. Using this, we demonstrated that melanoma cells produce superoxide anions, supporting previous observations which implicate superoxide anion in the mechanism of metastasis.
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PMID:Production of superoxide by human malignant melanoma cells. 983 50

We previously reported that reactive oxygen species (ROS) enhance tumor cell metastasis, and by administration of recombinant human superoxide dismutase (rh SOD), an enzyme which scavenges O2- successfully reduced lung metastasis of mouse MethA sarcoma and Lewis lung carcinoma. These observations suggested that rh SOD suppressed tumor cell invasion by eliminating O2- the primary source of ROS. However, for the clinical application of the drug as an anti metastatic agent, rh SOD needs to be administered in combination with other cytotoxic agents, since SOD by itself has no cytotoxic activity. In this paper, we investigated the effectiveness of the combination chemotherapy of rh SOD and adriamycin (ADR), an anti-cancer agent against the experimental metastasis of highly metastatic clone, MH-02, which was derived from murine Meth A sarcoma. The present metastasis experiment clearly indicates that the administration of rh SOD enhances the antimetastatic effect of ADR. On the other hand, we found that the inhibition rate of metastasis exhibited by the combination chemotherapy of rh SOD and a certain dose (5 mg/ml) of ADR was inferior to that of rh SOD. This apparent paradoxical phenomenon was presumably explained by our finding that tumor cells themselves augment their invasive capacity and platelet aggregation, both of which are causative factors for metastasis formation, by generation of O2- when they were treated with ADR. Nevertheless, the combination chemotherapy of SOD with anticancer drugs such as ADR can be a practical anti-metastasis strategy.
Clin Exp Metastasis 1999 May
PMID:Enhanced inhibition of experimental metastasis by the combination chemotherapy of Cu-Zn SOD and adriamycin. 1043 9

Platelet is blood's morphotic element in which intense energy metabolism takes place, which makes it possible to participate in the complex processes of the organism's homeostasis. The aim of the study was to analyse aerobic metabolism in the platelets, taking into consideration lipids peroxidation in patients with bladder cancer treated with the bacillus Calmette-Guerin (BCG) Mycobacterium suspension. The determination of superoxide dismutase (SOD-1) and malonyl dialdehyde (MDA) concentration activity constituted this evaluation's parameters. A group of 12 patients (4 women and 8 men) aged 54-67 years (average age 61) in which superficial bladder cancer was diagnosed were included in the study. Electroresection was carried out and subsequently, after 14 days, BCG Mycobacterium suspension was administered in intravesical instillations, in a 6-week cycle according to Morales. The material for the study was venous blood taken from the patients in three periods (before treatment, after the last clyster and 30 days after treatment) into the tubes with the addition of 1% EDTA in the ratio of 9 blood volumes to anticoagulant's one volume. Superoxide dismutase activity (Cu Zn--SOD) was determined according to Misra and Fridovich. The values were expressed in lamellar protein U/g protein. MDA concentration in platelet's TBARS was determined according to Pansa et al. MDA concentration included in TBARS was expressed in nmol/109 platelets. The controls were healthy volunteers in the same age range. In unaided studies a significant rise in superoxide dismutase (SOD-1) activity was obtained with the 1574.606 average before treatment > 2137.03 after treatment and 2646.4 after a month observation. Whereas MDA concentration increased in non-treated patients to 1.97, after treatment it dropped down significantly to 1.55 and sustained the downward trend after 30-day observation 1.4 nmol/109 platelets. The use of BCG intravesical clysters causes lipids peroxidation inhibition (decrease in MDA concentration) and the increase of SOD-1 activity results in smaller aggregation of platelets, preventing the formation of neoplastic metastases.
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PMID:[Lipids peroxidation in platelets in patients with bladder cancer treated with Mycobacterium suspension]. 1189 43

Selective inhibition of eicosanoid synthesis is thought to have effects on carcinogenesis in lung and colon cancer. However, it is still unknown whether pancreatic cancer might also be influenced. Therefore we evaluated the impact of selective cyclooxygenase-2 inhibitor Celebrex and selective 5-lipoxygenase inhibitor Zyflo on liver metastasis in a solid model of pancreatic adenocarcinoma in Syrian hamster. In week 33, the animals were sacrificed and incidence of pancreatic carcinomas and number and size of liver metastases were determined. Activities of antioxidative enzymes (GSHPX/SOD) and concentrations of products of lipidperoxidation were measured in liver metastases and non-metastatic hepatic tissue. The incidence (54.5 vs. 100%), number (3.17 +/- 0.98 vs. 6.75 +/- 0.71) and size (2.67 +/- 1.97 vs. 11.75 +/- 1.98 mm2) of liver metastases were decreased by combined therapy of Zyflo and Celebrex (P < 0.05). Furthermore, activities of GSHPX ([73.77 +/- 5.67]*10(5) vs. [15.49 +/- 4.02]*10(5) U/mg prot.; P < 0.05) and SOD (474.92 +/- 108.8 vs. 127.89 +/- 38.75 U/mg prot.; P < 0.05) were increased, while lipidperoxidation (0.31 +/- 0.08 nmol/mg prot. vs. 1.54 +/- 0.55 nmol/mg prot.; P < 0.05) was decreased by combination therapy, in non-metastatic hepatic tissue. Moreover, combined therapy increased lipidperoxidation in liver metastases (0.47 +/- 0.09 vs. 1.95 +/- 0.12 nmol/mg prot.; P < 0.05). Thus, a combination of Celebrex and Zyflo might be a new concept to decrease tumour growth in liver metastases in advanced pancreatic cancer.
Clin Exp Metastasis 2002
PMID:Effects of Celebrex and Zyflo on liver metastasis and lipidperoxidation in pancreatic cancer in Syrian hamsters. 1255 73

Renal cell carcinoma (RCC) is the tenth most common cancer although the incidence is increasing. The main clinical problems stem from the relatively late presentation of many patients due to the often asymptomatic nature of the illness, and the relative insensitivity of metastatic disease to conventional chemotherapy and radiotherapy. Despite increasing knowledge of some of the genetic changes underlying sporadic renal cancer such as those involving the Von Hippel Lindau (VHL) gene, many of the underlying pathophysiological changes are ill-defined and there remains a need for the identification of disease markers for use in diagnosis and prognosis or as potential therapeutic targets. This study has used a proteomic approach, based on two-dimensional gel electrophoresis and mass spectrometry, to compare the protein profiles of conventional RCC tissue with patient-matched normal kidney cortex. Sequencing of 32 protein spots with significantly increased expression in RCC samples (>/= 4/6 patients) and 41 proteins whose levels decreased (6/6 patients) confirmed several previously known RCC-associated changes such as increases in Mn-superoxide dismutase, lactate dehydrogenase-A, aldolase A and C, pyruvate kinase M2, and thymidine phosphorylase. Additionally, several previously unknown changes were identified, including increased expression of three members of the annexin family and increased levels of the actin depolymerisation factor cofilin. The Warburg effect was also demonstrated with the identification of increases in proteins involved in the majority of steps in the glycolytic pathway and decreases in the gluconeogenic reactions, together with a parallel decrease in several mitochondrial enzymes. A number of the alterations seen were further confirmed in additional samples by immunohistochemistry, Western blotting, and laser capture microdissection.
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PMID:Proteomic changes in renal cancer and co-ordinate demonstration of both the glycolytic and mitochondrial aspects of the Warburg effect. 1292 86

We carried out an open, non-randomized phase II study including all patients treated with whatever chemotherapy or combined modality regimen for whatever cancer who were in clinical objective response (complete response, CR, or partial response, PR) or stable disease (SD). The treatment consisted of administration of recombinant interleukin-2 (rIL-2) at a dose of 1.8 MIU subcutaneously three times/week (every other day) for the first 2 weeks of every month plus medroxyprogesterone acetate (MPA) 500 mg/day every other day plus antioxidant agents alpha-lipoic acid 300 mg/day and N-acetyl cysteine 1800 mg/day or carbocysteine lysine salt oral solution 2.7 g/day. The treatment was administered for 1 year except when progression of disease occurred. The primary study endpoints were to define clinical outcome, i.e. duration of response, survival (overall survival, OS and progression-free survival, PFS), the toxicity profile, and the evaluation of quality of life (QL). As secondary endpoints, we measured the changes of lymphocyte count, serum levels of proinflammatory cytokines, IL-2, C-reactive protein (CRP) and leptin, blood levels of reactive oxygen species (ROS) and antioxidant enzymes (glutathione peroxidase, GPx and superoxide dismertase, SOD). From July 1998 to June 2003, 42 patients were enrolled in the study (M/F ratio, 39/3; mean age, 62.5 years). Twenty (47.6%) patients were elderly (> 65 years). The majority of patients had either head and neck cancer or lung cancer, 88% had locally advanced or metastatic disease at diagnosis, and 76% had ECOG 0. Forty patients were previously treated with chemotherapy (27 also with radiotherapy), two with IL-2 and interfiron (IFN), one with endocrine therapy and one with only surgery. We obtained an objective response to maintenance treatment of 50%. Median duration of response was 19 months and median PFS was 33 months. Median duration of maintenance treatment was 12 months, median follow-up duration from diagnosis to June 2003 was 40 months, and median follow-up duration from study entry to June 2003 was 17 months. The median overall survival has not been reached. Toxicity was negligible. As for QL, a significant improvement of cognitive functions was observed, whereas all other functioning and symptom scales did not change significantly. As for laboratory parameters, absolute lymphocyte count increased significantly, IL-6, IL-1 beta, tumor necrosis factor-alpha, CRP, and fibrinogen decreased significantly whereas IL-2 and leptin increased significantly after treatment. ROS decreased significantly, whereas GPx increased significantly after treatment. Patients alive at study end showed a significant increase in absolute lymphocyte count, IL-2, leptin, and GPx and a significant decrease of proinflammatory cytokines, CRP, fibrinogen, and ROS, whereas patients who died before study end exhibited only a significant increase in absolute lymphocyte count, IL-2, and GPx and a significant decrease of ROS. Long-term combined maintenance therapy with rIL-2 + MPA + antioxidant agents is feasible, has a very low toxicity, and results in the improvement of clinical outcome, QL, and laboratory parameters.
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PMID:Subcutaneous interleukin-2 in combination with medroxyprogesterone acetate and antioxidants in advanced cancer responders to previous chemotherapy: phase II study evaluating clinical, quality of life, and laboratory parameters. 1456 91

To identify signature targets associated with patient-specific cancer lesions based on tumor versus normal tissue differential protein and mRNA coexpression patterns for the purpose of synthesizing cancer-specific customized RNA interference knockdown therapeutics. Analysis of biopsied tissue involved two-dimensional difference in-gel electrophoresis (2D-DIGE) analysis coupled with MALDI-TOF/TOF mass spectrometry for proteomic assessment. Standard microarray techniques were utilized for mRNA analysis. Priority was assigned to overexpressed protein targets with co-overexpressed genes with a high likelihood of functional nodal centrality in the cancer network as defined by the interactive databases BIND, HPRD and ResNet. HPLC-grade small interfering RNA (siRNA) duplexes were utilized to assess knockdown of target proteins in expressive cell lines as measured by western blot. Seven patients with metastatic cancer underwent biopsy. One patient (RW001) had biopsies from two disease sites 10 months apart. Seven priority proteins were identified, one for each patient (RACK 1, Ras related nuclear protein, heat-shock 27 kDa protein 1, superoxide dismutase, enolase1, stathmin1 and cofilin1). Prioritized proteins in RW001 from the two disease sites over time were the same. We demonstrated >80% siRNA inhibition of RACK 1 and stathmin1 of inexpressive malignant cell lines with correlated cell kill. Identification of functionally relevant target gene fingerprints, unique to an individual's cancer, is feasible 'at the bedside' and can be utilized to synthesize siRNA knockdown therapeutics. Further animal safety testing followed by clinical study is recommended.
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PMID:Proof concept for clinical justification of network mapping for personalized cancer therapeutics. 1754 24


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