Inhibition of prostate tumor growth and bone remodeling by the vascular targeting agent VEGF121/rGel.
The pathophysiology of tumor growth following skeletal metastases and the poor response of this type of lesion to therapeutic intervention remains incompletely understood. Vascular endothelial growth factor (VEGF)-A and its receptors play a role in both osteoclastogenesis and tumor growth. Systemic (i.v.) treatment of nude mice bearing intrafemoral prostate (PC-3) tumors with the vascular ablative agent VEGF(121)/recombinant gelonin (rGel) strongly inhibited tumor growth. Fifty percent of treated animals had complete regression of bone tumors with no development of lytic bone lesions. Immunohistochemical analysis showed that VEGF(121)/rGel treatment suppressed tumor-mediated osteoclastogenesis in vivo. In vitro treatment of murine osteoclast precursors, both cell line (RAW264.7) and bone marrow-derived monocytes (BMM), revealed that VEGF(121)/rGel was selectively cytotoxic to osteoclast precursor cells rather than mature osteoclasts. VEGF(121)/rGel cytotoxicity was mediated by Flt-1, which was down-regulated during osteoclast differentiation. Analysis by flow cytometry and reverse transcription-PCR showed that both BMM and RAW264.7 cells display high levels of Flt-1 but low levels of Flk-1. Internalization of VEGF(121)/rGel into osteoclast precursor cells was suppressed by pretreatment with an Flt-1 neutralizing antibody or by placenta growth factor but not with an Flk-1 neutralizing antibody. Thus, VEGF(121)/rGel inhibits osteoclast maturation in vivo and it seems that this process is important in the resulting suppression of skeletal osteolytic lesions. This is a novel and unique mechanism of action for this class of agents and suggests a potentially new approach for treatment or prevention of tumor growth in bone.
Mohamedali
Khalid A
KA
Department of Experimental Therapeutics and Genitourinary Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
Poblenz
Ann T
AT
Sikes
Charles R
CR
Navone
Nora M
NM
Thorpe
Philip E
PE
Darnay
Bryant G
BG
Rosenblum
Michael G
MG
D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D016723:Bone Remodeling / Q000187:drug effects*; D016923:Cell Death / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010010:Osteoclasts / Q000187:drug effects / Q000473:pathology; D010940:Plant Proteins / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011993:Recombinant Fusion Proteins / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D054789:Ribosome Inactivating Proteins, Type 1; D013552:Swine; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism
D010940:Plant Proteins; D011993:Recombinant Fusion Proteins; D054789:Ribosome Inactivating Proteins, Type 1; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C025674:GEL protein, Gelonium multiflorum; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1