title: The bisphosphonate olpadronate inhibits skeletal prostate cancer progression in a green fluorescent protein nude mouse model.
abstract: 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.
authors.affiliation: AntiCancer, Inc., San Diego, CA 92111, USA.
authors.forename: Meng
authors.initials: M
authors.lastname: Yang
authors.forename: Doug W
authors.initials: DW
authors.lastname: Burton
authors.forename: Jack
authors.initials: J
authors.lastname: Geller
authors.forename: Darren J
authors.initials: DJ
authors.lastname: Hillegonds
authors.forename: Randolph H
authors.initials: RH
authors.lastname: Hastings
authors.forename: Leonard J
authors.initials: LJ
authors.lastname: Deftos
authors.forename: Robert M
authors.initials: RM
authors.lastname: Hoffman
mesh_terms: 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*
chemical_list: 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