Zoledronic acid reduces bone loss and tumor growth in an orthotopic xenograft model of osteolytic oral squamous cell carcinoma.
Squamous cell carcinoma (SCC) is the most common form of oral cancer. Destruction and invasion of mandibular and maxillary bone frequently occurs and contributes to morbidity and mortality. We hypothesized that the bisphosphonate drug zoledronic acid (ZOL) would inhibit tumor-induced osteolysis and reduce tumor growth and invasion in a murine xenograft model of bone-invasive oral SCC (OSCC) derived from an osteolytic feline OSCC. Luciferase-expressing OSCC cells (SCCF2Luc) were injected into the perimaxillary subgingiva of nude mice, which were then treated with 100 μg/kg ZOL or vehicle. ZOL treatment reduced tumor growth and prevented loss of bone volume and surface area but had no effect on tumor invasion. Effects on bone were associated with reduced osteolysis and increased periosteal new bone formation. ZOL-mediated inhibition of tumor-induced osteolysis was characterized by reduced numbers of tartrate-resistant acid phosphatase-positive osteoclasts at the tumor-bone interface, where it was associated with osteoclast vacuolar degeneration. The ratio of eroded to total bone surface was not affected by treatment, arguing that ZOL-mediated inhibition of osteolysis was independent of effects on osteoclast activation or initiation of bone resorption. In summary, our results establish that ZOL can reduce OSCC-induced osteolysis and may be valuable as an adjuvant therapy in OSCC to preserve mandibular and maxillary bone volume and function.
Martin
Chelsea K
CK
Department of Veterinary Biosciences, Ohio State University, Columbus, Ohio 43214, USA.
Werbeck
Jillian L
JL
Thudi
Nanda K
NK
Lanigan
Lisa G
LG
Wolfe
Tobie D
TD
Toribio
Ramiro E
RE
Rosol
Thomas J
TJ
D000135:Acid Phosphatase; D000818:Animals; D050071:Bone Density Conservation Agents / Q000627:therapeutic use; D001862:Bone Resorption / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002118:Calcium / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002415:Cats; D004164:Diphosphonates / Q000627:therapeutic use*; D004195:Disease Models, Animal; D007093:Imidazoles / Q000627:therapeutic use*; D007527:Isoenzymes; D008156:Luciferases / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009062:Mouth Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects; D010014:Osteolysis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D000071681:Tartrate-Resistant Acid Phosphatase; D014183:Transplantation, Heterologous; D055114:X-Ray Microtomography; D000077211:Zoledronic Acid
D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D007527:Isoenzymes; D000077211:Zoledronic Acid; D008156:Luciferases; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase; D002118:Calcium