title: Apo2L/TRAIL inhibits tumor growth and bone destruction in a murine model of multiple myeloma.
abstract: OBJECTIVE
  Multiple myeloma is an incurable disease, for which the development of new therapeutic approaches is required. Here, we report on the efficacy of recombinant soluble Apo2L/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to inhibit tumor progression and bone destruction in a xenogeneic model of human multiple myeloma.
  
  
  METHODS
  We established a mouse model of myeloma, in which Apo2L/TRAIL-sensitive RPMI-8226 or KMS-11 cells, tagged with a triple reporter gene construct (NES-HSV-TK/GFP/Luc), were transplanted directly into the tibial marrow cavity of nude mice. Tumor burden was monitored progressively by bioluminescence imaging and the development of myeloma-induced osteolysis was measured using high resolution in vivo micro-computed tomography.
  
  
  RESULTS
  Tumor burden increased progressively in the tibial marrow cavity of mice transplanted with Apo2L/TRAIL-sensitive RPMI-8226 or KMS-11 cells associated with extensive osteolysis directly in the area of cancer cell transplantation. Treatment of mice with recombinant soluble Apo2L/TRAIL reduced myeloma burden in the bone marrow cavity and significantly protected against myeloma-induced osteolysis. The protective effects of Apo2L/TRAIL treatment on bone were mediated by the direct apoptotic actions of Apo2L/TRAIL on myeloma cells within the bone microenvironment.
  
  
  CONCLUSIONS
  This is the first in vivo study that investigates the efficacy of recombinant Apo2L/TRAIL on myeloma burden within the bone microenvironment and associated myeloma-induced bone destruction. Our findings that recombinant soluble Apo2L/TRAIL reduces myeloma burden within the bone microenvironment and protects the bone from myeloma-induced bone destruction argue against an inhibitory role of osteoprotegerin in Apo2L/TRAIL-induced apoptosis in vivo and highlight the need to clinically evaluate Apo2L/TRAIL in patients with multiple myeloma.
authors.affiliation: Discipline of Orthopaedics and Trauma, The University of Adelaide, Royal Adelaide Hospital, and Hanson Institute, South Australia, Australia.
authors.forename: Agatha
authors.initials: A
authors.lastname: Labrinidis
authors.forename: Peter
authors.initials: P
authors.lastname: Diamond
authors.forename: Sally
authors.initials: S
authors.lastname: Martin
authors.forename: Shelley
authors.initials: S
authors.lastname: Hay
authors.forename: Vasilios
authors.initials: V
authors.lastname: Liapis
authors.forename: Irene
authors.initials: I
authors.lastname: Zinonos
authors.forename: Natalie A
authors.initials: NA
authors.lastname: Sims
authors.forename: Gerald J
authors.initials: GJ
authors.lastname: Atkins
authors.forename: Cristina
authors.initials: C
authors.lastname: Vincent
authors.forename: Vladimir
authors.initials: V
authors.lastname: Ponomarev
authors.forename: David M
authors.initials: DM
authors.lastname: Findlay
authors.forename: Andrew C W
authors.initials: AC
authors.lastname: Zannettino
authors.forename: Andreas
authors.initials: A
authors.lastname: Evdokiou
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D051379:Mice; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D009368:Neoplasm Transplantation; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects; D010014:Osteolysis / Q000517:prevention & control*; D011994:Recombinant Proteins / Q000627:therapeutic use; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology / Q000627:therapeutic use*; D014183:Transplantation, Heterologous
chemical_list: D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand