Babatunde O Oyajobi1, Gregory R Mundy. 1. Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229-3900, USA. oyajobi@uthscsa.edu
Abstract
BACKGROUND: The bone destruction in myeloma patients is largely responsible for the clinical features of the disease. However, only recently has attention focused on identifying and developing drugs targeted specifically at the osteolysis. Receptor activator of NF-kappaB ligand (RANKL), macrophage inflammatory protein (MIP)-1alpha, and proteasomal function have been implicated in the pathogenesis of myeloma and associated bone disease. We provide "proof of principle" in preclinical myeloma models that these are indeed valid molecular targets in development of novel therapeutics. METHODS: The efficacy of antagonists of RANKL and MIP-1alpha bioactivities (RANK.Fc and neutralizing monoclonal anti-MIP-1alpha antibody) in ameliorating osteolysis and reducing tumor burden was evaluated in a mouse model in which murine myeloma 5TGM1 cells are injected intravenously into syngeneic mice. In addition, the activity of a petidyl aldehyde proteasome inhibitor (proteasome inhibitor-1 [PSI]) on tumor growth was tested in a murine 5TGM1 plasmacytoma model and in mice intravenously inoculated with 5TGM1 cells. RESULTS: RANK.Fc and anti-MIP-1alpha antibody inhibited the development and progression of osteolytic lesions and significantly reduced tumor load assessed by serum monoclonal paraprotein titers. Intratumoral injections of PSI inhibited growth of 5TGM1 plasmacytomas and induced tumor regression in some cases. In addition, systemic administration of PSI significantly prolonged time to onset of paraplegia in tumor-bearing mice. CONCLUSIONS: The results highlight the critical roles of RANKL and MIP-1alpha in the development and progression of myeloma and provide a basis for future evaluation in myeloma patients of novel therapeutics that disrupt interactions of RANKL and MIP-1alpha with their cognate receptors. The data also suggest that further studies in preclincal myeloma models aimed at identifying other proteasome inhibitors with antitumor efficacy would be worthwhile. Copyright 2003 American Cancer Society.DOI 10.1002/cncr.11133
BACKGROUND: The bone destruction in myelomapatients is largely responsible for the clinical features of the disease. However, only recently has attention focused on identifying and developing drugs targeted specifically at the osteolysis. Receptor activator of NF-kappaB ligand (RANKL), macrophage inflammatory protein (MIP)-1alpha, and proteasomal function have been implicated in the pathogenesis of myeloma and associated bone disease. We provide "proof of principle" in preclinical myeloma models that these are indeed valid molecular targets in development of novel therapeutics. METHODS: The efficacy of antagonists of RANKL and MIP-1alpha bioactivities (RANK.Fc and neutralizing monoclonal anti-MIP-1alpha antibody) in ameliorating osteolysis and reducing tumor burden was evaluated in a mouse model in which murinemyeloma 5TGM1 cells are injected intravenously into syngeneic mice. In addition, the activity of a petidyl aldehyde proteasome inhibitor (proteasome inhibitor-1 [PSI]) on tumor growth was tested in a murine 5TGM1 plasmacytoma model and in mice intravenously inoculated with 5TGM1 cells. RESULTS: RANK.Fc and anti-MIP-1alpha antibody inhibited the development and progression of osteolytic lesions and significantly reduced tumor load assessed by serum monoclonal paraprotein titers. Intratumoral injections of PSI inhibited growth of 5TGM1 plasmacytomas and induced tumor regression in some cases. In addition, systemic administration of PSI significantly prolonged time to onset of paraplegia in tumor-bearing mice. CONCLUSIONS: The results highlight the critical roles of RANKL and MIP-1alpha in the development and progression of myeloma and provide a basis for future evaluation in myelomapatients of novel therapeutics that disrupt interactions of RANKL and MIP-1alpha with their cognate receptors. The data also suggest that further studies in preclincal myeloma models aimed at identifying other proteasome inhibitors with antitumor efficacy would be worthwhile. Copyright 2003 American Cancer Society.DOI 10.1002/cncr.11133
Authors: Robert E Coleman; Theresa A Guise; Allan Lipton; G David Roodman; James R Berenson; Jean-Jacques Body; Brendan F Boyce; Laura M Calvi; Peyman Hadji; Eugene V McCloskey; Fred Saad; Matthew R Smith; Larry J Suva; Russell S Taichman; Robert L Vessella; Katherine N Weilbaecher Journal: Clin Cancer Res Date: 2008-10-15 Impact factor: 12.531
Authors: Claire M Edwards; James R Edwards; Seint T Lwin; Javier Esparza; Babatunde O Oyajobi; Brandon McCluskey; Steven Munoz; Barry Grubbs; Gregory R Mundy Journal: Blood Date: 2007-12-19 Impact factor: 22.113
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