The bisphosphonate olpadronate inhibits skeletal prostate cancer progression in a green fluorescent protein nude mouse model.

Abstract

PURPOSE:

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.

EXPERIMENTAL DESIGN:

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: Meng Yang, Doug W Burton, Jack Geller, Darren J Hillegonds, Randolph H Hastings, Leonard J Deftos, Robert M Hoffman
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 12 Issue 8 Pg. 2602-6 (Apr 15 2006) ISSN: 1078-0432 [Print] United States
• PMID: 16638872 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Bone Density Conservation Agents
• Diphosphonates
• Glycoproteins
• Osteoprotegerin
• Parathyroid Hormone-Related Protein
• Receptors, Cytoplasmic and Nuclear
• Receptors, Tumor Necrosis Factor
• TNFRSF11B protein, human
• Tnfrsf11b protein, mouse
• Green Fluorescent Proteins
• olpadronic acid
• Pamidronate
• Calcium

Topics

• Animals
• Bone Density Conservation Agents (therapeutic use)
• Bone Neoplasms (metabolism, prevention & control, secondary)
• Calcium (blood)
• Cell Line, Tumor
• Diphosphonates (therapeutic use)
• Disease Progression
• Glycoproteins (blood)
• Green Fluorescent Proteins (genetics, metabolism)
• Humans
• Male
• Mice
• Mice, Nude
• Osteoprotegerin
• Pamidronate
• Parathyroid Hormone-Related Protein (blood)
• Prostatic Neoplasms (drug therapy, metabolism, pathology)
• Receptors, Cytoplasmic and Nuclear (blood)
• Receptors, Tumor Necrosis Factor (blood)
• Time Factors
• Treatment Outcome
• Xenograft Model Antitumor Assays (methods)