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Chemical Compound Review

LOXORIBINE     2-amino-9-[(2R,3R,4S,5R)-3,4- dihydroxy-5...

Synonyms: Loxoribina, Loxoribinum, SureCN61782, CHEMBL292008, RWJ-21757, ...
 
 
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Disease relevance of RWJ 21757

 

High impact information on RWJ 21757

  • Topology of the loxoribine binding site. Studies with inactive loxoribine analogues [5].
  • These data suggest that one mechanism by which cytolytic precursor cells are primed by loxoribine to respond to IL-2 faster and with enhanced cytolytic activity may be through the expression of high affinity IL-2 receptors due to the up-regulation of the alpha-chain [6].
  • Analysis of the expression of the alpha-chain of the IL-2 receptor after loxoribine stimulation indicated that gene transcription was enhanced within 4 h, and cell surface expression was observed on NK1.1+ Thy1+ and NK1.1+ Thy1- cell populations within 24 h of loxoribine treatment [6].
  • The priming of LAK cell precursors by loxoribine did not appear to be mediated by IFN-alpha/beta, because anti-IFN antibodies did not block either the activation of cytolytic cells by IL-2 or the expression of IL-2 receptors after culture with loxoribine [6].
  • The Toll-like receptor 7 (TLR7)-specific stimulus loxoribine uncovers a strong relationship within the TLR7, 8 and 9 subfamily [7].
 

Chemical compound and disease context of RWJ 21757

 

Biological context of RWJ 21757

  • We conducted a double-blind randomized phase I study to evaluate the safety, pharmacokinetics, and immunologic effects of single ascending doses of loxoribine in patients with advanced cancer [8].
  • Prolonged exposure of B-CLL cells to stimulatory concentrations of loxoribine frequently culminates in progression of the responsive cells to apoptosis [9].
  • Evaluation of in vivo activity has been undertaken only for antibody production, NK cell-mediated cytotoxicity, induction of certain cytokines, and LAK cell-mediated cytotoxicity; all four types of activity are markedly upregulated by loxoribine in vivo [10].
 

Anatomical context of RWJ 21757

  • Loxoribine (7-allyl-8-oxoguanosine) activates natural killer cells and primes cytolytic precursor cells for activation by IL-2 [6].
  • Here we first demonstrate that loxoribine activates cells of the innate immune system selectively via the Toll-like receptor (TLR) 7/MyD88-dependent signaling pathway [7].
  • Subsequently we show that cellular activation by loxoribine and resiquimod (R-848), a stimulus for TLR7 and TLR8, depends on acidification and maturation of endosomes and targets MyD88 to vesicular structures with lysosomal characteristics [7].
  • In this paper we examined a disubstituted guanosine, 7-allyl-8-oxoguanosine (loxoribine), for the ability to activate NK cells and to interact with IL-2 in the generation of LAK cells in vivo [3].
  • First, the levels of cytokine mRNA in spleens from vehicle- or loxoribine-treated mice were compared using PCR analysis with a panel of cytokine-specific primers [11].
 

Associations of RWJ 21757 with other chemical compounds

  • 7-Allyl-8-oxoguanosine (loxoribine) is a di-substituted guanine ribonucleoside which has been shown previously to enhance murine NK activity, B lymphocyte proliferation, and antibody synthesis [12].
  • There were significantly greater numbers of dendritic cells in the explants of animals treated with loxoribine and levamisole [4].
  • TLR7 recognizes small synthetic immune modifiers including imiquimod, R-848, loxoribine, and bropirimine, all of which are already applied or promising for clinical use against viral infections and cancers [13].
 

Gene context of RWJ 21757

  • The bacterial TLR agonists (PAM, PGN, LPS, and FGN) all induced an up-regulation of expression of mRNA of the pro-inflammatory cytokines IL-1beta, IL-6, and IL-8; whereas both poly(I:C) and LOX induced a down-regulation of these cytokine mRNAs [14].
  • These data suggest that, although several cytokines are produced in response to loxoribine, only IFN-alpha and IFN-beta are directly involved in the NK activation and proliferative responses [12].
  • U0126 increased loxoribine-induced expression of IL-12 p40 and IL-12 p70 in B10.S but not SJL/J macrophages [15].
  • Loxoribine induced more IL-12 p70 production and p35 expression in B10.S than SJL/J macrophages [15].
  • The chicken TLR7+ HD11 cell line and fresh splenocytes produced elevated levels of interleukin-1beta (IL-1beta) mRNA after exposure to the agonists R848 and loxoribine [16].
 

Analytical, diagnostic and therapeutic context of RWJ 21757

  • Slow and continuous administration of loxoribine via subcutaneously implanted infusion pumps successfully enhanced the NK activity for several days after all of the pump contents had been delivered [17].

References

  1. Loxoribine induces chronic lymphocytic leukemia B cells to traverse the cell cycle. Goodman, M.G., Wormsley, S.B., Spinosa, J.C., Piro, L.D. Blood (1994) [Pubmed]
  2. 7-Allyl-8-oxoguanosine (loxoribine) inhibits the metastasis of B16 melanoma cells and has adjuvant activity in mice immunized with a B16 tumor vaccine. Pope, B.L., Sigindere, J., Chourmouzis, E., MacIntyre, P., Goodman, M.G. Cancer Immunol. Immunother. (1994) [Pubmed]
  3. In vivo activation of natural killer cells and priming of IL-2 responsive cytolytic cells by loxoribine (7-allyl-8-oxoguanosine). Pope, B.L., Chourmouzis, E., Sigindere, J., MacIntyre, J.P., Capetola, R.J., Lau, C.Y. Cell. Immunol. (1993) [Pubmed]
  4. Regression of endometrial explants in a rat model of endometriosis treated with the immune modulators loxoribine and levamisole. Keenan, J.A., Williams-Boyce, P.K., Massey, P.J., Chen, T.T., Caudle, M.R., Bukovsky, A. Fertil. Steril. (1999) [Pubmed]
  5. Topology of the loxoribine binding site. Studies with inactive loxoribine analogues. Goodman, M.G., Goodman, J.H. J. Immunol. (1994) [Pubmed]
  6. Loxoribine (7-allyl-8-oxoguanosine) activates natural killer cells and primes cytolytic precursor cells for activation by IL-2. Pope, B.L., Chourmouzis, E., Victorino, L., MacIntyre, J.P., Capetola, R.J., Lau, C.Y. J. Immunol. (1993) [Pubmed]
  7. The Toll-like receptor 7 (TLR7)-specific stimulus loxoribine uncovers a strong relationship within the TLR7, 8 and 9 subfamily. Heil, F., Ahmad-Nejad, P., Hemmi, H., Hochrein, H., Ampenberger, F., Gellert, T., Dietrich, H., Lipford, G., Takeda, K., Akira, S., Wagner, H., Bauer, S. Eur. J. Immunol. (2003) [Pubmed]
  8. Phase 1, randomized, double-blind trial of 7-allyl-8-oxoguanosine (loxoribine) in advanced cancer. Agarwala, S.S., Kirkwood, J.M., Bryant, J. Cytokines Cell. Mol. Ther. (2000) [Pubmed]
  9. New perspectives on the approach to chronic lymphocytic leukemia. Goodman, M.G., Spinosa, J.C., Saven, A., Piro, L.D., Wormsley, S. Leuk. Lymphoma (1996) [Pubmed]
  10. A new approach to vaccine adjuvants. Immunopotentiation by intracellular T-helper-like signals transmitted by loxoribine. Goodman, M.G. Pharmaceutical biotechnology. (1995) [Pubmed]
  11. The immunostimulatory compound 7-allyl-8-oxoguanosine (loxoribine) induces a distinct subset of murine cytokines. Pope, B.L., MacIntyre, J.P., Kimball, E., Lee, S., Zhou, L., Taylor, G.R., Goodman, M.G. Cell. Immunol. (1995) [Pubmed]
  12. Murine strain variation in the natural killer cell and proliferative responses to the immunostimulatory compound 7-allyl-8-oxoguanosine: role of cytokines. Pope, B.L., Chourmouzis, E., MacIntyre, J.P., Lee, S., Goodman, M.G. Cell. Immunol. (1994) [Pubmed]
  13. Recognition of pathogen-associated molecular patterns by TLR family. Akira, S., Hemmi, H. Immunol. Lett. (2003) [Pubmed]
  14. Expression and function of Toll-like receptors in chicken heterophils. Kogut, M.H., Iqbal, M., He, H., Philbin, V., Kaiser, P., Smith, A. Dev. Comp. Immunol. (2005) [Pubmed]
  15. Disparate expression of IL-12 by SJL/J and B10.S macrophages during Theiler's virus infection is associated with activity of TLR7 and mitogen-activated protein kinases. Petro, T.M. Microbes Infect. (2005) [Pubmed]
  16. Identification and characterization of a functional, alternatively spliced Toll-like receptor 7 (TLR7) and genomic disruption of TLR8 in chickens. Philbin, V.J., Iqbal, M., Boyd, Y., Goodchild, M.J., Beal, R.K., Bumstead, N., Young, J., Smith, A.L. Immunology (2005) [Pubmed]
  17. In vivo enhancement of murine natural killer cell activity by 7-allyl-8-oxoguanosine (loxoribine). Pope, B.L., Chourmouzis, E., Sigindere, J., Capetola, R.J., Lau, C.Y. Int. J. Immunopharmacol. (1992) [Pubmed]
 
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