Disease relevance of RWJ 21757

• Loxoribine induces chronic lymphocytic leukemia B cells to traverse the cell cycle [1].
• In this study, we examined loxoribine for protective effects in a B16 melanoma lung tumor metastasis model [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 [2].
• Mature B and T cells were not required for NK activation since SCID mice responded to loxoribine within the same dose range as did the normal, immunocompetent mice [3].
• CONCLUSION(S): Loxoribine, a potent immunomodulatory drug, appeared to cause regression in both stromal and epithelium components in a rat model of endometriosis [4].

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

• Leukemic B cells from a majority of patients with chronic lymphocytic leukemia (CLL) enter the cell cycle upon stimulation in vitro with loxoribine, a potent 7,8-disubstituted guanine ribonucleoside immunostimulant [1].

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