The bisphosphonate olpadronate inhibits skeletal prostate cancer progression in a green fluorescent protein nude mouse model.
OBJECTIVE
Metastatic bone disease is one of the major causes of morbidity and mortality in prostate cancer patients. Bisphosphonates are currently used to inhibit bone resorption and reduce tumor-induced skeletal complications. More effective bisphosphonates would enhance their clinical value.


METHODS
We tested several bisphosphonates in a green fluorescent protein (GFP)-expressing human prostate cancer nude mouse model. The in vivo effects of four bisphosphonates, including pamidronate, etidronic acid, and olpadronate, on bone tumor burden in mice intratibially inoculated with PC-3-GFP human prostate cancer cells were visualized by whole-body fluorescence imaging and X-ray.


RESULTS
The PC-3-GFP cells produced extensive bone lesions when injected into the tibia of immunocompromised mice. The skeletal progression of the PC-3-GFP cell growth was monitored by GFP fluorescence and the bone destruction was evaluated by X-ray. We showed that 3,3-dimethylaminopropane-1-hydroxy-1,1-diphosphonic acid (olpadronate) was the most effective bisphosphonate treatment in reducing tumor burden as assessed by GFP imaging and radiography. The GFP tumor area and X-ray score significantly correlated. Reduced tumor growth in the bone was accompanied by reduced serum calcium, parathyroid hormone-related protein, and osteoprotegerin.


CONCLUSIONS
The serum calcium, parathyroid hormone-related protein, and osteoprotegerin levels were significantly correlated with GFP area and X-ray scores. Treatment with olpadronate reduced tumor growth in the bone measured by GFP and X-ray imaging procedures. Imaging of GFP expression enables monitoring of tumor growth in the bone and the GFP results complement the X-ray assessment of bone disease. The data in this report suggest that olpadronate has potential as an effective inhibitor of the skeletal progression of clinical prostate cancer.
Yang
Meng
M
AntiCancer, Inc., San Diego, CA 92111, USA.
Burton
Doug W
DW
Geller
Jack
J
Hillegonds
Darren J
DJ
Hastings
Randolph H
RH
Deftos
Leonard J
LJ
Hoffman
Robert M
RM
D000818:Animals; D050071:Bone Density Conservation Agents / Q000627:therapeutic use; D001859:Bone Neoplasms / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary; D002118:Calcium / Q000097:blood; D045744:Cell Line, Tumor; D004164:Diphosphonates / Q000627:therapeutic use*; D018450:Disease Progression; D006023:Glycoproteins / Q000097:blood; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D053244:Osteoprotegerin; D000077268:Pamidronate; D044162:Parathyroid Hormone-Related Protein / Q000097:blood; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018160:Receptors, Cytoplasmic and Nuclear / Q000097:blood; D018124:Receptors, Tumor Necrosis Factor / Q000097:blood; D013997:Time Factors; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays / Q000379:methods*
D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D006023:Glycoproteins; D053244:Osteoprotegerin; D044162:Parathyroid Hormone-Related Protein; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C506030:TNFRSF11B protein, human; C506031:Tnfrsf11b protein, mouse; D049452:Green Fluorescent Proteins; C055774:olpadronic acid; D000077268:Pamidronate; D002118:Calcium