J.
Cancer Mol. 4: 175-181, 2009
[Research
Paper]
Prolonged Antiresorptive Treatment of Lytic Prostate Cancer Xenografts
in Mouse Bone Results in Tumor Necrosis
J. M. Blair, J. R. K. Modzelewski, L. A. Perryman, P. J. Russell, M. J.
Seibel, and C. R. Dunstan
Bone
Research Program, ANZAC Research Institute, University of Sydney at
Concord, Concord NSW 2139, Australia [J. M. Blair, J. R. K. Modzelewski,
M. J. Seibel]; Oncology Research Centre, University of New South Wales
Department of Clinical Medicine, Prince of Wales Hospital, Randwick NSW
2031, Australia [L. A. Perryman, P. J. Russell]; Biomedical Engineering,
AMME, University of Sydney, Sydney, NSW 2006, Australia [C. R. Dunstan]
Abstract:
AIM:
In this study, we examine the time dependence of commencing
antiresorptive treatments, using an Fc-fusion osteoprotegerin construct
(Fc-OPG), on the growth, viability and lytic effects of PC3 human
prostate cancer xenografts in male mouse bone.
METHODS:
Male mice were implanted with PC3 cells by intratibial injection. Mice
were randomized into three groups (n = 5-7 per group) to receive vehicle
or 3 mg/kg Fc-OPG three times weekly from the week before cell injection
(week -1; early treatment), week 0 (simultaneous treatment) or week 2
(delayed treatment).
RESULTS:
When compared with vehicle-treated controls, Fc-OPG treatments protected
bone and reduced bone turnover marker levels. In early and simultaneous
Fc-OPG treated mice, necrosis of bone-enclosed tumor and the adjacent
endosteal bone was observed. No tissue or bone necrosis was seen in
sham-injected or vehicle-treated controls or in the contralateral tibiae
of Fc-OPG treated mice.
CONCLUSION:
The
necrosis of bone-confined tumor in Fc-OPG-treated mice suggests that
prolonged blockage of bone erosion during the early development of a
tumor mass in bone can limit vascular supply, leading to necrosis. The
loss of osteocyte viability was only seen adjacent to necrotic tumor,
which suggests that this effect is not due to bone resorption inhibition
per se but to interactions between inhibition of bone resorption
and tumor effects.
(Keywords:
osteoprotegerin; bone resorption; bone metastasis; RANK ligand)
Received 9/15/08; Revised 12/2/08; Accepted 12/15/08.
1Correspondence:
Dr. Colin R. Dunstan, Biomedical Engineering, AMME JO7, University of
Sydney, Sydney, NSW 2006, Australia. Phone: 61-2-93517127. Fax:
61-2-93517060. E-mail:
c.dunstan@usyd.edu.au
2Abbreviations:
CaP, prostate cancer; RANKL, RANK ligand; OPG, osteoprotegerin; TRAP5b,
tartrate-resistant acid phosphatase type 5b; microCT, microtomography;
BV, bone volume; ONJ, osteonecrosis of the jaw.
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