Comparison of Fc-osteoprotegerin and zoledronic acid activities suggests that zoledronic acid inhibits prostate cancer in bone by indirect mechanisms.
Zoledronic acid (ZA) has been shown to inhibit prostate tumor growth in vitro and have beneficial effects in patients with advanced prostate cancer (CaP). The aim of this study was to determine whether ZA exhibits direct anti-tumor effects on CaP cells in vivo. To distinguish the effects of inhibition of osteolysis and direct anti-tumor activity of ZA in vivo, we compared the results of treatment with ZA and osteoprotegerin (Fc-OPG), which inhibits osteolysis, but without significant direct anti-tumor effects. In vitro Fc-OPG had no significant effects on C4-2 proliferation, whereas ZA decreased proliferation. However, both agents decreased tumor growth in bone. Moreover, both increased bone volume and prevented the overall decreases in BMD associated with growth of C4-2 cells in bone. Our study provides novel and significant observations that the in vivo effects of ZA are consistent with indirect effects mediated by osteoclasts.
Department of Urology, University of Washington, Seattle, Washington 98195, USA.
J E
JE
Quinn
L G
LG
Brown
J
J
Zhang
E T
ET
Keller
R L
RL
Vessella
E
E
Corey
D000818:Animals; D000906:Antibodies / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis; D015519:Bone Density; D050071:Bone Density Conservation Agents / Q000494:pharmacology; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000556:secondary*; D049109:Cell Proliferation; D003720:Densitometry; D004164:Diphosphonates / Q000737:chemistry / Q000494:pharmacology*; D006023:Glycoproteins / Q000737:chemistry* / Q000276:immunology* / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D007141:Immunoglobulin Fc Fragments / Q000627:therapeutic use*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D010010:Osteoclasts / Q000378:metabolism; D010014:Osteolysis; D053244:Osteoprotegerin; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry* / Q000276:immunology*; D018124:Receptors, Tumor Necrosis Factor / Q000737:chemistry* / Q000276:immunology*; D013977:Tibia / Q000473:pathology; D013997:Time Factors; D000077211:Zoledronic Acid
D000906:Antibodies; D000970:Antineoplastic Agents; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D006023:Glycoproteins; D007093:Imidazoles; D007141:Immunoglobulin Fc Fragments; D053244:Osteoprotegerin; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C506030:TNFRSF11B protein, human; C506031:Tnfrsf11b protein, mouse; D000077211:Zoledronic Acid