Disease relevance of Linomide

• CONCLUSIONS: Linomide is unique among the antiangiogenic agents tested, in that it inhibits the stimulatory effects of TAMs on tumor angiogenesis without eliminating their antiangiogenic effects, and may thus prove to be more effective against prostate cancer [1].
• However, all of the agents reduced tumor blood vessel density and tumor growth, with Linomide being the most effective (44% reduction in blood vessel density and 69% inhibition of tumor growth) [1].
• In this study we examined the effect of linomide (80 mg per kg per day in drinking water) on mice with chronic-relapsing experimental autoimmune encephalomyelitis (CR-EAE), a T-cell-mediated organ-specific autoimmune disease that resembles human multiple sclerosis [2].
• Treatment of chronic-relapsing experimental autoimmune encephalomyelitis with the synthetic immunomodulator linomide (quinoline-3-carboxamide) [2].
• Since linomide is very well tolerated in experimental animals and humans, it might be used in the treatment of multiple sclerosis [2].

Psychiatry related information on Linomide

• In conclusion, LS 2616 has potent antitumor activities mediated by NK cells as well as non-NK cell related defense mechanisms [3].

High impact information on Linomide

• These results suggest that linomide prevents cell death triggered by Fas ligation and can be useful for therapeutic intervention in fulminant hepatitis [4].
• Surviving mice showed severe depletion of cortical thymocytes, but medullar thymic cells expressing high CD3 and Fas levels also survived the treatment with anti-Fas in the presence of linomide [4].
• Linomide is a synthetic immunomodulator that enhances natural killer cell activity and significantly activates several lymphocytic cell subpopulations in both experimental animals and humans [2].
• These results suggest that linomide regulates autoimmunity in the absence of systemic immunosuppression [2].
• Lymphocytes obtained from linomide-treated mice had a reduced in vitro proliferative response to the myelin basic protein and to the tuberculin purified protein derivative, whereas the mitogenic response to concanavalin A was not affected [2].

Chemical compound and disease context of Linomide

• These studies demonstrated that linomide treatment decreases microvessel density in both androgen-independent human prostatic cancers [5].
• The effects of LS-2616 on longevity, as well as on development of lymphadenopathy, splenomegaly, glomerulonephritis, and vasculitis, were pronounced and were comparable with those of cyclophosphamide [6].
• In peripheral T cells, linomide also prevents apoptosis triggered by a variety of stimuli, including superantigens, dexamethasone and vaccinia virus [7].
• Linomide activates the adrenocortical axis in the rat: inhibition of experimental autoimmune encephalomyelitis by linomide is not related to the increase of corticosterone [8].
• The therapeutic effects of ABR-215062, which is a new immunoregulator derived from Linomide, have been evaluated in experimental autoimmune neuritis (EAN), a CD4(+) T cell-mediated animal model of Guillain-Barré syndrome in man [9].

Biological context of Linomide

• Linomide is a low molecular weight, water-soluble agent with excellent p.o. absorption and bioavailability [10].
• Prevention of autoimmune diabetes by linomide in nonobese diabetic (NOD) mice is associated with up-regulation of the TCR-mediated activation of p21(ras) [11].
• Examination of the target cell spectrum lysed by spleen effector cells during Linomide treatment as well as studies of phenotype, clearly indicated that the effector cells studied were NK cells [12].
• We, therefore, conclude that prevention of autoimmune diabetes by linomide is associated with up-regulation of the p21(ras) T cell signal transduction defect in NOD mice [11].
• CONCLUSIONS: The combination of linomide's properties, namely, blockage of proinflammatory cytokine and NO production, as well as prevention of apoptosis, is of paramount interest, making linomide a potential candidate for combating HIV-1 infection or preventing some of its associated pathological manifestations [7].

Anatomical context of Linomide

• Linomide treatment protected mice from passively induced CR-EAE as well, when given from the day of injection with myelin-basic-protein-specific lymphocytes [2].
• Linomide-treated animals were also resistant to an induced attack by a booster injection with a murine spinal cord homogenate [2].
• None of the mice (n = 17) that were treated with linomide from day 7 after disease induction developed any clinical or histopathological signs of CR-EAE, as compared to 19 of 20 untreated controls that were severely paralyzed and had extensive demyelinating lesions in the central nervous system [2].
• The carboxamide-quinoline LS 2616 is a novel immunomodulator augmenting natural killer (NK) cell activity and T-lymphocyte related effector functions [3].
• Treatment of rats with linomide decreases significantly (P < 0.05), by more than 50%, the number of tumor associated macrophages within both locally invasive (i.e., from 20-40 to 10 macrophages/high power field) and highly metastatic primary prostatic cancers (i.e., from 60-70 to 15-37 macrophages/high power field) [13].

Associations of Linomide with other chemical compounds

• In addition, when rats were treated with linomide and than challenged with lipopolysaccharide in vivo, the resulting elevation in serum TNF-alpha was inhibited by approximately 50% (i.e., 4.56 +/- 1.8 ng/ml of TNF-alpha in control versus 2.9-2.2 ng/ml depending upon the dose of linomide) [13].
• However, Poly I:C, in contrast to LS 2616, increased NK activity in peritoneal exudate cells [14].
• Abolition of the effect of cyclosporine on rat cardiac allograft rejection by the new immunomodulator LS-2616 (Linomide) [15].
• Moreover, Linomide reduced aspartate aminotransferase by 87-97%, and alanine aminotransferase by 79-96% [16].
• We assessed the effect of Linomide on microvascular perfusion failure, leukocyte recruitment and hepatocellular injury induced by tumor necrosis factor alpha (TNF-alpha) and D-Galactosamine (Gal) [16].

Gene context of Linomide

• Linomide is unable to inhibit either basal or hypoxia-induced secretion of VEGF [17].
• Linomide also has no effect on secreted bFGF levels [17].
• Linomide also prevents human TNF-alpha and IFN-gamma production, as well as iNOS expression and affects the viral load, promoting potent suppression of HIV-1 infectivity as detected in peritoneal cavity and spleen [7].
• Administration of Linomide inhibited endotoxin-induced gene expression of MIP-2 and KC and significantly reduced the hepatic production of MIP-2 and KC by 63 and 80%, respectively [18].
• The novel immunomodulator, Linomide, stimulates interleukin-2-induced human natural killer (NK) cell and PHA-stimulated T cell proliferation from normal donors [19].

Analytical, diagnostic and therapeutic context of Linomide

• In this study we determined the effect of oral treatment with linomide on the development of experimental autoimmune encephalomyelitis, an animal model for immune-mediated human demyelinating disorders [20].
• To investigate the possible usefulness of LS 2616 in immunotherapy of tumors, the effect of the substance on growth and metastasis of the B16-F10 melanoma in syngeneic C57BL/6 mice was investigated [3].
• When given in combination, castration potentiated the inhibition of tumor growth induced by Linomide alone [17].
• Linomide could therefore be of use in future clinical trials for the treatment of human autoimmune demyelinating disorders [20].
• We have previously demonstrated that daily p.o. treatment with Linomide has antiangiogenic abilities against a series of rat and human prostatic cancer xenografts growing in vivo [10].

References