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Effect of zoledronic acid therapy in an in vivo model of bone invasive feline oral squamous cell carcinoma

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Title: Effect of zoledronic acid therapy in an in vivo model of bone invasive feline oral squamous cell carcinoma
Creators: Martin, Chelsea
Advisor: Rosol, Thomas
Issue Date: 2009-04
Abstract: Objective: To test the hypothesis that zoledronic acid will inhibit tumor-induced osteolysis and reduce tumor growth and invasion in a xenograft mouse model of bone invasive oral squamous cell carcinoma (OSCC). In humans, OSCC is the 6th most common cancer in the world. Bone invasion frequently occurs and is associated with poor prognosis and reduced survival. OSCC is the most commonly diagnosed malignancy of the oral cavity in cats and has a grave prognosis with an average duration of survival of only 2 months. Feline OSCC (FOSCC) is very aggressive and commonly invades bone, which is characterized by osteoclastic bone resorption. Zoledronic acid (ZOL) is a potent third generation nitrogen-containing bisphosphonate which inhibits osteoclastic bone resorption. There are currently no available treatment modalities which significantly improve prognosis or prolong survival of cats with FOSCC. Methods: A luciferase-expressing FOSCC cell line (SCCF2Luc) was injected into the perimaxillary subgingival lamina propria of 30 athymic nude mice. Mice were treated with 100 µg/kg ZOL, or vehicle, twice weekly for 4 weeks. Thirty non-tumor-bearing mice served as controls. Tumor growth was monitored with in vivo bioluminescent imaging and tumor dimensions were determined with calipers. The degree of bone loss was evaluated using faxitron radiography and micro-computed tomography (microCT). A 2mm thick region of interest (ROI) in the rostral skull, incorporating the xenograft and adjacent pre-maxillary and maxillary bone, was selected using µCT and image analysis software. ROI-bone surface area and bone volume were calculated and compared between treatment groups. Tumor invasiveness was evaluated microscopically. Osteolysis and osteoclast activation were evaluated with TRAP histochemistry and histomorphometry. Results and conclusions: Progressive xenograft growth occurred in all mice, as indicated by increasing bioluminescence. Bioluminescence was positively correlated with tumor volume. ZOL treatment significantly reduced tumor growth (in vivo bioluminescence), prevented loss of bone volume and surface area (microCT), and was associated with reduced osteolysis and increased periosteal new bone formation (microCT, faxitron radiography and histomorphometry). ZOL had no effect on tumor invasion around the incisor or into the nasal cavity. ZOL-mediated inhibition of tumor-induced osteolysis was characterized by significantly reduced numbers of TRAP-positive osteoclasts at the tumor-bone interface and was associated with osteoclast vacuolar degeneration. The ratio of eroded to total bone surface was not significantly affected by treatment; indicating that ZOL-mediated inhibition of osteolysis was independent of osteoclast activation and maturation. Significance: This preclinical model of OSCC recapitulates the bone invasive phenotype characteristic of the disease in both humans and cats, and will be useful to future preclinical studies of bone invasive OSCC regardless of species. ZOL reduced FOSCC-induced osteolysis and bioluminescence, but invasive behavior was unchanged. The results of this experiment suggest that ZOL monotherapy would be of limited clinical use in the management of FOSCC, but may be valuable as adjunct therapy with the purpose of maintaining mandibular and maxillary bone volume and function.
Embargo: A three-year embargo was granted for this item.
Series/Report no.: 2009 Edward F. Hayes Graduate Research Forum. 23rd
Keywords: mouse model
oral squamous cell carcinoma
feline
osteociastic bone resorption
bisophosphonate
zoledronic acid
Description: Professional Biological Sciences: 1st Place (The Ohio State University Edward F. Hayes Graduate Research Forum)
URI: http://hdl.handle.net/1811/45369
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Attribution-NonCommercial-NoDerivs 3.0 Unported