Abstract：
:Bisphosphonates (BPs), bone targeted drugs that disrupt osteoclast function, are routinely used to treat complications of bone metastasis. Studies in preclinical models of cancer have shown that BPs reduce skeletal tumor burden and increase survival. Similarly, we observed in the present study that administration of the Nitrogen-containing BP (N-BP), zoledronic acid (ZA) to osteolytic tumor-bearing Tax+ mice beginning at 6 months of age led to resolution of radiographic skeletal lesions. N-BPs inhibit farnesyl diphosphate (FPP) synthase, thereby inhibiting protein prenylation and causing cellular toxicity. We found that ZA decreased Tax+ tumor and B16 melanoma viability and caused the accumulation of unprenylated Rap1a proteins in vitro. However, it is presently unclear whether N-BPs exert anti-tumor effects in bone independent of inhibition of osteoclast (OC) function in vivo. Therefore, we evaluated the impact of treatment with ZA on B16 melanoma bone tumor burden in irradiated mice transplanted with splenic cells from src(-/-) mice, which have non-functioning OCs. OC-defective mice treated with ZA demonstrated a significant 88% decrease in tumor growth in bone compared to vehicle-treated OC-defective mice. These data support an osteoclast-independent role for N-BP therapy in bone metastasis.
journal_name
Bonejournal_title
Boneauthors
Hirbe AC,Roelofs AJ,Floyd DH,Deng H,Becker SN,Lanigan LG,Apicelli AJ,Xu Z,Prior JL,Eagleton MC,Piwnica-Worms D,Rogers MJ,Weilbaecher Kdoi
10.1016/j.bone.2009.01.010subject
Has Abstractpub_date
2009-05-01 00:00:00pages
908-16issue
5eissn
8756-3282issn
1873-2763pii
S8756-3282(09)00015-5journal_volume
44pub_type
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