Roquinimex

Roquinimex (Linomide; PNU212616; ABR212616) is a quinoline derivative immunostimulant which increases NK cell activity and macrophage cytotoxicity; inhibits angiogenesis and reduces the secretion of TNF alpha. IC50 value: Target: TNF alpha Prophylactic administration of DSS-treated mice with roquinimex significantly reduced clinical signs of colitis, MDS and the CH-reduction. Moreover, in roquinimex treated animals, the MPO activity was significantly reduced by more than 50% compared to DSS control mice. Notably, therapeutic administration of roquinimex in DSS-treated mice also significantly inhibited the MDS, CH-reduction and MPO activity [2]. Linomide, a synthetic immunomodulator, at concentrations effective in vivo reduces the number of MBP-reactive TNF-alpha and increases MBP-reactive IL-10 and TGF-beta mRNA expressing MNC from MS patients' blood when analysed in vitro. Compared to dexamethasone, Linomide up-regulated levels of blood MNC expressing mRNA of TGF-beta after culture in presence of MBP [3].

References:
[1]. Roquinimex, From Wikipedia [2]. Liu Q, et al. Roquinimex inhibits dextran sodium sulfate-induced murine colitis. Inflamm Res. 2003 Feb;52(2):64-8. [3]. Tian WZ, et al. Linomide (roquinimex) affects the balance between pro- and anti-inflammatory cytokines in vitro in multiple sclerosis. Acta Neurol Scand. 1998 Aug;98(2):94-101.

Reduced gingival fluid flow: a peripheral marker of the pharmacological effect of roquinimex.[Pubmed:15035809]

Inflammopharmacology. 2003;11(3):267-76.

OBJECTIVE: Roquinimex is a drug with effects on inflammation and tumors. The pharmacological effect is not fully understood, and the molecular mechanism most characterized in vitro is an increase of plasminogen activator inhibitor type 2 (PAI-2) in human peripheral blood monocytes. The aims were to investigate peripheral pharmacological effects of Roquinimex on peripheral blood monocytes and dog gingival fluid (GCF). DESIGN: Six dogs were used in a cross-over study. The amount of GCF was determined with a Periotron. The PAI-2 concentration in GCF was determined with ELISA. Monocytes were isolated from peripheral blood. RESULTS: Dogs treated with the drug had significantly lower GCF flow values and the PAI-2 concentration in GCF was higher, but no effect was seen on peripheral monocytes. CONCLUSION: Roquinimex treatment led to a consistently decreased flow rate of GCF and a higher local concentration of PAI-2 in GCF.

Roquinimex-mediated protection effect on the development of chronic graft-versus-host disease in mice is associated with induction of Th1 cytokine production and inhibition of proinflammatory cytokine production.[Pubmed:17950363]

Life Sci. 2007 Oct 27;81(19-20):1403-10.

Roquinimex is an immunomodulator that can effectively inhibit the development of several autoimmune diseases in animal models, but the mechanism is still unknown. In this study, we investigated the effect of Roquinimex on chronic graft-versus-host disease (GVHD) in mice, a well-established model for human systemic lupus erythematosus (SLE). Oral administration of Roquinimex significantly suppressed the development of proteinuria and ameliorated nephritis symptoms in chronic GVHD mice. In addition, renal histopathology and immunohistochemistry studies revealed reduced glomerulonephritis and decreased IgG deposition in chronic GVHD mice treated with Roquinimex. Chronic GVHD is characterized by a predominance of Th2 cytokines, and proinflammatory cytokines that also play an important role in the pathology of tissue damage. Therefore, we focused on the effect of Roquinimex on cytokine production. Chronic GVHD mouse splenocytes exhibited severely reduced interferon (IFN)-gamma production in response to Concanavalin (Con A) stimulation and an overt Th2 skewness. Roquinimex treatment, however, induced IFN-gamma production and restored the Th1/Th2 cytokine balance, although only a minimal effect of Roquinimex on interleukin (IL)-4 secretion was observed. The production of the proinflammatory cytokines TNF-alpha and IL-1 beta by peritoneal macrophages from lipopolysaccharide (LPS)-treated GVHD mice was significantly inhibited by Roquinimex treatment. These data suggested that the beneficial effect of Roquinimex on lupus might, at least in part, result from a restoration of Th1/Th2 cytokine balance and inhibition of inflammatory cytokine production.

Immunomodulation by roquinimex decreases the expression of IL-23 (p19) mRNA in the brains of herpes simplex virus type 1 infected BALB/c mice.[Pubmed:15270847]

Clin Exp Immunol. 2004 Aug;137(2):305-12.

Herpes simplex virus (HSV) is a common neurotropic virus which infects epithelial cells and subsequently the trigeminal ganglia (TG) and brain tissue. We studied how immunomodulation with Roquinimex (Linomide) affects the course of corneal HSV infection in BALB/c mice. BALB/c mice have also been used in a model for HSV-based vectors in treating an autoimmune disease of the central nervous system (CNS). We addressed the questions of how immunomodulation affects the local as well as the systemic immune response and whether Roquinimex could facilitate the spread of HSV to the CNS. The cytokine response in the brain and TG was studied using a quantitative rapid real-time RT-PCR method. We were interested in whether immunomodulation affects the expression of the recently described Th1-cytokine IL-23p19 in the brain and TG. The expression of IL-23 mRNA was decreased in brains of Roquinimex-treated BALB/c mice. Also the expression of IL-12p35 and IFN-gamma mRNAs decreased. No significant changes were seen in IL-4 and IL-10 mRNA expression. The cytokine response was also studied using supernatants of stimulated splenocytes by EIA. Roquinimex treatment suppressed the production of IFN-gamma and also the production of IL-10 in HSV-infected BALB/c mice.

Roquinimex inhibits dextran sodium sulfate-induced murine colitis.[Pubmed:12665123]

Inflamm Res. 2003 Feb;52(2):64-8.

OBJECTIVE: Roquinimex is a modulator of the immune system and has been shown to attenuate induction of several inflammatory and autoimmune diseases. The objective of the present study was to determine the efficacy of Roquinimex in a model of murine colitis. MATERIALS AND METHODS: For this purpose, Balb/c mice were exposed to 5% dextran sodium sulfate (DSS) in the drinking water for five to six days. Roquinimex (300 mg kg(-1) day(-1)) was administered by subcutaneous (s.c.) injection 3 days prior to and throughout the treatment period with DSS. In separate experiments, 300 mg kg(-1) day(-1) of Roquinimex was given therapeutically after initiation of DSS challenge. RESULTS: DSS provoked clinical signs of colitis, reduced crypt height (CH) and increased mucosal damage score (MDS) as analyzed by histology. In addition, challenge with DSS increased the colonic content of myeloperoxidase (MPO). Prophylactic administration of DSS-treated mice with Roquinimex significantly reduced clinical signs of colitis, MDS and the CH-reduction. Moreover, in Roquinimex treated animals, the MPO activity was significantly reduced by more than 50% compared to DSS control mice. Notably, therapeutic administration of Roquinimex in DSS-treated mice also significantly inhibited the MDS, CH-reduction and MPO activity. CONCLUSIONS: These findings suggest that Roquinimex strongly inhibits murine colitis and may provide a novel pharmacological approach to treat inflammatory bowel disease.

Linomide inhibits programmed cell death of peripheral T cells in vivo.[Pubmed:8020570]

Eur J Immunol. 1994 Jan;24(1):48-52.

Programmed cell death (PCD) is involved in the physiological regulation of lymphocyte turnover, as well in the antigen-driven selection of T and B cells. Here it is shown that the immunomodulator linomide (quinoline-3-carboxamide) inhibits the apoptotic decay of peripheral T lymphocytes in response to three different stimuli. First, linomide reduces the superantigen-mediated apoptosis and deletion of specific T lymphocytes of both the CD4+ and the CD8+ subsets without affecting other superantigen-triggered phenomena such as T cell expansion and anergy. Second, linomide abolishes the T lymphopenia and inhibits PCD of splenic CD4+ and CD8+ T cells induced by exogenous glucocorticoids. This effect is restricted to peripheral T lymphocytes and does not concern thymocytes. Finally, linomide abolishes the development of lymphopenia that follows infection with vaccinia virus, while reducing PCD of CD4+ and CD8+ peripheral T cells. The anti-apoptotic effect of linomide could account for its immunostimulatory properties and might be relevant to the treatment of immunodeficiencies associated with an increased apoptotic decay of T lymphocytes.

Antiangiogenic effects of the quinoline-3-carboxamide linomide.[Pubmed:7682157]

Cancer Res. 1993 Apr 15;53(8):1833-7.

Linomide (N-phenylmethyl-1,2-dihydro-4-hydroxyl-1-methyl-2-oxoquinoline-3-carboxa mide) has a reproducible in vivo antitumor effect against a series of both androgen responsive and independent Dunning R-3327 rat prostatic cancers. This antitumor effect of linomide is host mediated. One possible mechanism involving the host is that linomide has antiangiogenic activity. An indication that linomide treatment has antiangiogenic activity is the observation that prostatic cancers from linomide treated rats have more focal necrosis than sized matched tumors from untreated rats. To directly test if linomide has antiangiogenic activity, a newly developed Matrigel based quantitative in vivo angiogenic assay was used. These experiments demonstrated that linomide has dose dependent, antiangiogenic activity in vivo in the rat. Additional studies demonstrated that due to its antiangiogenic activity, linomide treatment of rats bearing prostate cancers resulted in a more than 40% decrease in tumor blood flow. Blood flow to a variety of non-tumor bearing organs was not decreased suggesting that linomide selectively inhibits angiogenesis and does not induce loss of established blood vessels. Using as a model the response of human umbilical vein endothelial cells to linomide treatment in a variety of in vitro assays, linomide was demonstrated to have cytostatic but not cytotoxic effect on human umbilical vein endothelial cells at a medium concentration of > or = 100 micrograms/ml. In addition, both endothelial cell chemotactic migration and invasion are steps in angiogenesis inhibited by linomide treatment.

The antitumor effects of the quinoline-3-carboxamide linomide on Dunning R-3327 rat prostatic cancers.[Pubmed:1591718]

Cancer Res. 1992 Jun 1;52(11):3022-8.

Linomide (N-phenylmethyl-1,2-dihydro-4-hydroxyl-1-methyl-2-oxo-quinoline-3- carboxamide) is a quinoline 3-carboxamide which previously has been demonstrated to produce immunomodulator and antitumor effects when given in vivo. To test the possible antitumor effects of linomide against prostatic cancers, rats bearing five distinct Dunning R-3327 rat prostatic cancer sublines were treated daily with i.p. injections of linomide. These studies demonstrated that linomide has a reproducible antitumor effect against all of the prostatic cancers tested regardless of their growth rate, degree of morphologic differentiation, metastatic ability, or androgen responsiveness. This antitumor effect is observed only in vivo, not in vitro, and involves a cytotoxic response of the prostatic cancer cells. This cytotoxic response results in the retardation of the growth rate (i.e., increased tumor volume doubling time) of primary prostatic cancers and in metastatic lesions. Linomide's growth retardation is reversible, and thus continuous daily treatment with linomide is required for maximal antitumor response. Pretreatment of rats with linomide before tumor inoculation has no effect in addition to that produced by initiating linomide treatment at the time of tumor inoculation. No enhancement of either natural killer cell number or natural killer cell cytotoxic activity is induced by linomide treatment in the tumor-bearing rats. In addition, depletion of natural killer cell activity via injections of asialo-GM1 antiserum does not prevent the antitumor effects of linomide in vivo. Likewise, the antitumor effects of linomide are also produced in prostatic cancer-bearing athymic nude rats. These results suggest that the requirement for host involvement in the antitumor effects of linomide against rat prostatic cancers may involve both immune and nonimmune host mechanism(s) (e.g., antiangiogenesis).

Roquinimex (Linomide; PNU212616; ABR212616) is a quinoline derivative immunostimulant which increases NK cell activity and macrophage cytotoxicity; inhibits angiogenesis and reduces the secretion of TNF alpha.

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