This mathematical model was tested in a combined group of patients with MM and metastatic RCC, thus confirming the validity of this mathematical modeling that predicted the range of efficacy of antiCIL-6 MAbs

This mathematical model was tested in a combined group of patients with MM and metastatic RCC, thus confirming the validity of this mathematical modeling that predicted the range of efficacy of antiCIL-6 MAbs. Conclusions The experimental evidence linking IL-6 to the pathogenesis of a variety of cancers emphasizes the potential role of this cytokine in targeted biologic therapies. antiCinterleukin-6 mAb on cancer-related anorexia and cachexia may also be of clinical significance in a vast number of cancer patients. was proposed.Poupart, Vandenabeele, et al. 1987 36238/id The physiologic activity of IL-6 is complex, producing both pro-inflammatory and anti-inflammatory effects in the immune system (Figure 1). Interleukin-6 promotes inflammation by contributing to the proliferation and activation of T cells, stimulating the differentiation of B cells, and inducing the acute-phase reactants Rabbit polyclonal to FDXR of the hepatocyte population.Jones, Horiuchi, et al. 2001 36225/id In contrast, IL-6 inhibits aspects of the inflammatory cascade also. Both of the two primary inflammatory cytokines, tumor necrosis factor alpha (TNF-) and IL-1, stimulate the production of prostaglandins, nitric oxide, and matrix metalloproteinases. Interleukin-6, on the other hand, does not promote the production of these inflammatory mediators, and it is hypothesized that IL-6 may play a role in regulating or turning off the in vivo synthesis of TNF- and IL-1.Barton 1997 32109/id Despite these functions, IL-6 modulates the transcription of several liver-specific genes during acute inflammatory states, particularly C-reactive protein (CRP), and controls the proliferation of normal plasmablastic cells, as demonstrated in reactive plasmacytosis by using monoclonal antibody (mAb) directed against IL-6 Gavarotti, Boccadoro, et al. 1985 38022/idIn addition, IL-6 has been shown to be an activator or an inhibitor of T-cell responses, depending on the target and the operational system used in vitro. This intricate interaction of pro-inflammatory and anti-inflammatory activities hints at the critical role IL-6 potentially plays in regulating the physiologic response to disease. Open in a separate window Figure 1 Physiologic activity of interleukin-6 (NGF, nerve growth factor). Increased production of IL-6 has been implicated in a variety of disease processes, including neoplasia, Alzheimers disease, autoimmunity (e.g., rheumatoid arthritis), inflammation, myocardial infarction, aging, Pagets disease, osteoporosis, neoplasia (renal cell carcinoma [RCC], prostatic and bladder cancers, certain neurologic cancers), B-cell malignancies (e.g., Castlemans disease), some lymphoma subtypes, and, particularly, multiple myeloma (MM) Keller, Wanagat, et al. 1996 36226/idSimpson, Hammacher, et al. 1997 35743/idTupitsyn, Kadagidze, et al. 1998 36232/id. In addition, IL-6 is implicated in proliferation pathways as a central proliferation factor or acting in cooperation with other factors, such as heparin-binding epithelial growth factor and hepatocyte growth factor (Oncogene 2002, 21:460; Cancer Res 2001, 61: 383; 2002 38024/idThis reinforces the hypothesis that blocking IL-6 might have significant benefit in a large variety of pathologic situations.} {In the following discussion we review the role of IL-6 in the etiology and pathogenesis of cancer,|In the following discussion we review the role of IL-6 in the pathogenesis and etiology of cancer,} as well as a comprehensive review of clinical trials of targeted cancer therapy using mAb to IL-6. Interleukin-6/Interleukin-6 Receptor Interaction Interleukin-6 is a multifunctional cytokine that binds to a specific IL-6 receptor ( chain, IL-6R, or CD126) on target cells. This IL-6/IL6R complex associates with two molecules of the ubiquitously expressed gp130 FzM1.8 ( chain, CD130), the second chain of the receptor, resulting in the formation of high-avidity IL-6 binding receptors {Kishimoto, Akira, et al. 1992 38003/id}; {Ward, Howlett, et al. 1994 38023/id}The gp130 functions as an affinity converter, since the resulting affinity of IL-6 for the ternary complex is around 10?11 M, {instead of FzM1.8 10?|of 10 instead?}9 M for IL-6R. {Whereas gp80 binds specifically to IL-6,|Whereas gp80 binds to IL-6 specifically,} gp130 is a common signal-transducing receptor for a subfamily of cytokines, including IL-6, IL-11, leukemia-inhibiting factor (LIF), ciliary neurotrophic factor (CNTF), oncostatin M (OM), and cardiotropin 1 (CT-1), named the gp130 cytokine family. After binding to their specific receptors, all these cytokines induce homodimerization of gp130 or its heterodimerization with the LIF receptor (LIFR), which initiates cell signaling {Kishimoto, Akira, et al. 1992 38003/id}. In contrast with the wide distribution of gp130, gp80 is limited to hepatocytes and specialized subsets of leukocytes, including monocytes, neutrophils, T cells, and B cells (Jones et al 2001). Stimulation of gp130 is essential for hematopoiesis in vivo. {The system is complicated by the presence of soluble forms of both gp80 and gp130.|The operational system is complicated by the presence of soluble forms of both gp80 and gp130.} These circulating compounds are cleaved from the cell membrane molecule or translated from an alternative spliced mRNA, yielding a FzM1.8 protein that differs at its COOH-terminus by 14 amino-acid residues {Mullberg, Schooltink, et al. 1993 38008/id}{Horiuchi, Koyanagi, et al. 1994 38030/id}. Cleavage of transmembrane proteins can be done by a transmembrane metalloproteinase, distinct from matrix-type metalloproteases,.