Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0003864 (arthritis)
 69,039 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Piroxicam is a nonsteroidal anti-inflammatory drug (NSAID) widely used for treatment of inflammatory arthritis. Recent experimental and clinical studies suggest that piroxicam, as well as other NSAIDs, may be useful for chemoprevention of colon cancer. While there is less information regarding NSAIDs for chemoprevention of urinary bladder malignancy, there are compelling data which suggest that this should be evaluated. A major effect of NSAIDs is inhibition of cyclooxygenase, the rate-limiting enzyme for conversion of arachidonic acid to important signal molecules, including prostaglandins, which profoundly affect cellular functions in many tissues. The initial enzyme reaction leading to formation of prostaglandin H can be accompanied by cooxidation of xenobiotics resulting in extrahepatic and local tissue production of reactive products which are carcinogenic. The end product prostaglandins, especially prostaglandin E2 (PGE2), are biological modifiers which can significantly affect cell proliferation and tumor growth. High levels of PGE2 stimulate growth of certain tumor cell lines while inhibition of prostaglandin synthesis with indomethacin or piroxicam can cause suppression. The mechanisms for this effect are unclear. Studies in cultured cells exposed to indomethacin show inhibition of G1-to-S phase progression of the cell cycle and a reduction in overall DNA synthesis. It is unclear whether this effect on cell growth results from some direct action of the NSAID or a reduction in prostaglandins or indirectly from modulation of important control signals, such as calcium flux. In addition to cyclooxygenase, NSAIDs can inhibit activity of other enzymes, including phosphodiesterases and cyclic GMP-AMP protein kinases, which may be central to cancer initiation and promotion. NSAIDs can also interfere with transmembrane ion fluxes and with cell-to-cell binding. Prostaglandins can modulate a variety of immunological responses and thereby play an important role in host antitumor immunity. For example, high levels of tissue PGE2 are frequently associated with suppression of immune surveillance and killing of malignant cells. Conversely, immune responses are generally enhanced by drugs that inhibit prostaglandin synthesis. PGE2 can act as a feedback inhibitor for cellular immune processes, such as T-cell proliferation, lymphokine production, and cytotoxicity. This effect is also seen for macrophage activity and natural killer cell toxicity. In general, either increased production of PGE2 or increased sensitivity to normal amounts of PGE2 results in depressed cellular immunity. Cyclooxygenase inhibitors (NSAIDs) such as piroxicam which decrease PGE2 production can stimulate cellular immune function both in vitro and in vivo. A variety of tumor cell lines and human malignancies produce large quantities of prostaglandins.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Piroxicam and other cyclooxygenase inhibitors: potential for cancer chemoprevention. 130 81

The hypothesis that tumors are angiogenesis dependent has, in the past decade, generated new investigations designed to elucidate the mechanism of angiogenesis itself. Many laboratories are now engaged in this pursuit. Some are studying angiogenesis that occurs in physiological situations, whereas others are interested in angiogenesis that dominates pathological conditions. These efforts have led to (1) the development of bioassays for angiogenesis; (2) the partial purification and, in one case, the complete purification of angiogenic factors from neoplastic and non-neoplastic cells; (3) the development of new polymer technology for the sustained release of these factors and other macromolecules in vivo; (4) the cloning and long-term culture of capillary endothelial cells; (5) the demonstration of the role of nonendothelial cells, such as mast cells in modulating angiogenesis; (6) the discovery of angiogenesis inhibitors; and (7) the demonstration that certain animal tumors will regress when angiogenesis is inhibited. The effects of angiogenesis inhibitors provide perhaps the most compelling evidence for the role of angiogenesis in tumor growth. It is conceivable that the original effort to understand the role of angiogenesis in tumor growth will also lead to the use of angiogenesis inhibitors as a new class of pharmacologic agents in a variety of non-neoplastic diseases such as arthritis, psoriasis, and ocular neovascularization. However, much work remains to be done before it will be possible to understand (1) the regulatory systems that govern capillary density in normal tissues; (2) the factors that maintain the viability of microvascular endothelium; (3) the development of the vascular system itself; and (4) the mechanism by which vascular regression occurs, both in the embryo and in the postnatal organism. A knowledge of the mechanisms which underlie these normal processes may help to enlarge our comprehension of tumor angiogenesis.
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PMID:Tumor angiogenesis. 258 24

Serotoninergic contractions of the rat stomach strip were evoked and EC50 determined. In preparations from control animals MDP, 50 mumol/l, decreased EC50 or sensitized the preparation. In the strips from animals where adjuvant arthritis was induced, higher sensitivity to 5-HT was observed and the sensitizing effect of MDP was retained. In the strips from animals pretreated with cyclophosphamide or in the terminal stage of tumor growth lower sensitivity to 5-HT, which could be further decreased by MDP, were noticed. These opposite effects in serotoninergic reactions were tentatively linked with the modulation of the immune status in vivo.
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PMID:The influence of immune status on the in vitro sensitivity of serotoninergic receptors in the rat stomach strip. 348 12

The family of tissue inhibitors of metalloproteinases (TIMPs) presently numbers four distinct gene products that are specific inhibitors of the matrix metalloproteinases (MMPs). The local balance between MMPs and TIMPs is believed to play a major role in extracellular matrix (ECM) remodeling during development and in diseases such as cancer and arthritis. Unlike the other TIMPs, which are soluble. TIMP-3 is unique in being a component of ECM. Mutations in the human TIMP-3 gene cause a dominantly inherited, adult-onset blindness (Sorsby's fundus dystrophy or SFD). In this article, we summarize what is currently known about TIMP-3, discuss possible mechanisms leading up to SFD, and investigate the effect of TIMP-3 on tumor growth. Breast carcinoma and malignant melanoma cell lines were transfected with TIMP-3 expression plasmids and injected subcutaneously into nude mice. Growth curves of the resulting tumors over a period of 6 to 8 weeks demonstrated that increased expression of TIMP-3 resulted in a statistically significant suppression of tumor growth. Deposition of TIMP-3 in the surrounding ECM by tumor cells may inhibit tumor growth by preventing local expansion of tumor, retarding the release of growth factors sequestered in ECM, or inhibiting angiogenesis. TIMP-3 over-expression had no effect on the growth of the two tumor cell lines in vitro. Because recombinant TIMP-3 inhibits endothelial cell migration and tube formation in response to angiogenic factors, we believe that the effect of TIMP-3 on tumor growth seen in this study may be a consequence of its angiostatic action.
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PMID:A review of tissue inhibitor of metalloproteinases-3 (TIMP-3) and experimental analysis of its effect on primary tumor growth. 916 53

Cytogenin (8-hydroxy-3-hydroxymethyl-6-methoxyisocoumarin) is a new microbial product with antitumor and antirheumatoid arthritis effects in vivo when administered orally, although its mechanism(s) of action is not known well. Both neoplasia and rheumatoid arthritis are referred to as angiogenesis-dependent diseases. The aim of the present study was to investigate the effects of cytogenin on both physiological and pathological angiogenesis, using the growing chick embryo chorioallantoic membrane and mouse dorsal air sac assay systems, respectively. The microbial product at doses up to 100 micrograms/egg did not significantly affect embryonic angiogenesis when topically placed on the surface of the chorioallantoic membrane, suggesting that it has no effect on the physiological (or normal) angiogenic response. By contrast, systemic administration of cytogenin (100 mg/kg p.o., for 5 consecutive days) significantly suppressed angiogenesis induced by malignant tumor cells (S-180), one of pathological neovascularization, in a mouse dorsal air sac assay system. Pharmacokinetic studies in mice revealed that the maximal concentration of cytogenin in plasma after a single 100 mg/kg oral dose of the compound was 32 microM. In vitro experiments involving cultured vascular endothelial cells showed that cytogenin at concentrations determined by pharmacokinetic study, had little effect on plasminogen activator secretion, tube formation and the proliferation of endothelial cells. These results suggest that cytogenin is a novel oral antiangiogenic agent, that the mechanism of its antiangiogenic action contributes to its suppressive effects on both tumor growth and rheumatoid arthritis that we previously found, and that it could be developed as a potential therapeutic agent for cancer, rheumatoid arthritis and other angiogenesis-dependent disorders such as diabetic retinopathy.
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PMID:Effects of cytogenin, a novel microbial product, on embryonic and tumor cell-induced angiogenic responses in vivo. 921 39

Mounting evidence suggests that lipoxygenase (LO)-catalyzed products have a profound influence on the development and progression of human cancers. Compared with normal tissues, significantly elevated levels of LO metabolites have been found in lung, prostate, breast, colon, and skin cancer cells, as well as in cells from patients with both acute and chronic leukemias. LO-mediated products elicit diverse biological activities needed for neoplastic cell growth, influencing growth factor and transcription factor activation, oncogene induction, stimulation of tumor cell adhesion, and regulation of apoptotic cell death. Agents that block LO-catalyzed activity may be effective in preventing cancer by interfering with signaling events needed for tumor growth. In fact, in a few studies, LO inhibitors have prevented carcinogen-induced lung adenomas and rat mammary gland cancers. During the past 10 years, pharmacological agents that specifically inhibit the LO-mediated signaling pathways are now commercially available to treat inflammatory diseases such as asthma, arthritis, and psoriasis. These well-characterized agents, representing two general drug effect mechanisms, are considered good candidates for clinical chemoprevention studies. One mechanism is inhibition of LO activity (5-LO and associated enzymes, or 12-LO); the second is leukotriene receptor antagonism. Although the receptor antagonists have high potential in treating asthma and other diseases where drug effects are clearly mediated by the leukotriene receptors, enzyme activity inhibitors may be better candidates for chemopreventive intervention, because inhibition of these enzymes directly reduces fatty acid metabolite production, with concomitant damping of the associated inflammatory, proliferative, and metastatic activities that contribute to carcinogenesis. However, because receptor antagonists have aerosol formulations and possible antiproliferative activity, they may also have potential, particularly in the lung, where topical application of such formulations is feasible.
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PMID:Lipoxygenase inhibitors as potential cancer chemopreventives. 1035 Apr 44

The proteolytic activity of the matrix metalloproteinases (MMPs) involved in extracellular matrix degradation must be precisely regulated by their endogenous protein inhibitors, the tissue inhibitors of metalloproteinases (TIMPs). Disruption of this balance can result in serious diseases such as arthritis and tumor growth and metastasis. Knowledge of the tertiary structures of the proteins involved in such processes is crucial for understanding their functional properties and to interfere with associated dysfunctions. Within the last few years, several three-dimensional structures have been determined showing the domain organization, the polypeptide fold, and the main specificity determinants of the MMPs. Complexes of the catalytic MMP domains with various synthetic inhibitors enabled the structure-based design and improvement of high-affinity ligands, which might be elaborated into drugs. Very recently, structural information also became available for some TIMP structures and MMP-TIMP complexes, and these new data elucidated important structural features that govern the enzyme-inhibitor interaction.
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PMID:Insights into MMP-TIMP interactions. 1041 21

Groups of CBA mice immunosuppressed with anti-thymocyte serum (ATS) treatment were xeno-transplanted with either HeLa human cervical carcinoma cells or genetically modified cells expressing the human tumor necrosis factor-alpha (TNF) gene (All cells). Both cell lines were highly resistant to the cytotoxic effects of TNF. If 3 x 10(6) tumor cells were inoculated s.c. into female mice, HeLa cells grew progressively into large tumors and killed 74% of the recipients, while TNF-expressing All cells caused fatal tumor growth only in 22% of the mice. 3 x 10(6) or 1.5 x 10(7). All cells produced progressive tumor growth and lethality in all male recipients. In sera of all the A11-cell-transplanted mice, biologically active TNF was detected shortly (4.5 h) after tumor inoculation (6 39 U/ml), decreasing to below detection level in the circulation by day 3. In recipients of 15 million A11 cells, circulating TNF reappeared and reached high levels (12-1000 U/ml) 3 to 7 weeks later, when the animals bore large tumors (14-23 mm). Generally, such mice became cachectic, severely anemic, hypothermic, and soon died. On account of calcium mobilization from bones, their serum Ca levels were high. Electron microscopy revealed severe liver damage, but there were no signs of chronic arthritis. These results suggest that ATS-treated mice xenotransplanted with TNF-gene-transfected A11 human tumor cells provide a new model for studying the pathophysiological and anti-tumor effects of TNF.
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PMID:Pathophysiological effects of human TNF-alpha-producing tumor xenografts in immunosuppressed mice. 1054 87

Angiogenesis, the process by which new blood vessels are generated, occurs during wound healing, in the female reproductive system during ovulation and gestation, and during embryonic development. The process is carefully controlled with positive and negative regulators, because several vital physiological functions require angiogenesis. The consequences of abnormal angiogenesis are either excessive or insufficient blood vessel growth. Ulcers, strokes, and heart attacks can result from the absence of angiogenesis normally required for natural healing, whereas excessive blood vessel proliferation may favor tumor growth and dissemination, blindness, and arthritis. In this review, the process of angiogenesis and the characteristics of the resulting tumor vasculature are outlined. Contrast-enhanced magnetic resonance imaging techniques that currently are available for basic research and clinical applications to study various aspects of tumor angiogenesis and neovascularization are discussed.
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PMID:Tumor angiogenesis, vascularization, and contrast-enhanced magnetic resonance imaging. 1055 24

Matrix metalloproteinases (MMP) are a group of zinc dependent enzymes which include the interstitial collagenases, stromelysins, gelatinases and membrane-type metalloproteinases. They are involved in the remodelling and turnover of the extracellular matrix proteins. They play a role in wound healing and the pathogenesis of arthritis. In malignancies they play a role in tumor invasion, metastasis and angiogenesis. A number of synthetic matrix metalloproteinase inhibitors (MMPIs) have been developed for clinical use. In preclinical tumor models they have shown promising activity in achieving inhibition of MMPs and reducing tumor growth and metastatic spread. Some have also shown additive or synergistic effects with cytotoxic agents. Phase I and II studies in human subjects have defined the main side effects of these agents as being musculoskeletal pains or arthralgias. As they are cytostatic agents rather than cytotoxic in activity conventional measurements of radiological response for assessment are not applicable in trials. Biological activity has been demonstrated in certain cancers by the effects on levels of tumor markers as surrogate markers of tumor response and also by a fibrotic stromal reaction seen in tumor tissue. Newer agents have been developed with selective inhibition of certain MMPs in an attempt to reduce the side effects. A number of phase III human clinical trials evaluating MMPs are being carried out at present but only one has been formally reported so far. This study suggested that marimastat had no survival advantage when compared to chemotherapy with gemcitabine in advanced pancreatic carcinoma. Current trials are assessing efficacy of MMPIs in maintenance of remission after other modalities of therapy or in combination with cytotoxic agents. MMPs have also been demonstrated to play an important role in the articular cartilage destruction seen in both rheumatoid arthritis and osteoarthritis. The use of MMPIs in both ex vivo and in vivo models have shown promising results and trials are in process to assess their potential role in the control of articular destruction. The true therapeutic role of MMPIs await the results of these randomized studies.
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PMID:Matrix metalloproteinase inhibitors: applications in oncology. 1075 5


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