ABSTRACT
Introduction:
Zoledronic acid (ZOL) is a third-generation
bisphosphonate with a higher affinity for
bone resorption areas than earlier
bisphosphonates (i.e.,
pamidronate, PAM). In
human medicine, ZOL provides improved
bone pain relief and prolonged
time to skeletal-related events compared to its older generational counterparts. Preclinical studies have investigated its
role as an anti-neoplastic agent, both independently and synergistically, with
radiation therapy (RT). ZOL and RT act synergistically in several neoplastic
human cell lines prostate,
breast,
osteosarcoma, and
fibrosarcoma. However, the exact mechanism of ZOL's radiosensitization has not been fully elucidated.
Methods:
We investigated ZOL's
ability to induce
apoptosis in canine
osteosarcoma cell lines treated with various doses of megavoltage external beam
radiotherapy. Second, we evaluated
cell cycle arrest in ZOL-treated
cells to assess several neo-adjuvant
time points. Finally, we treated 20
dogs with naturally occurring appendicular OS with 0.1 mg/kg ZOL IV 24 h before receiving 8 Gy of RT (once weekly fraction x 4 weeks).
Results:
We found that
apoptosis was increased in all ZOL-treated
cell lines compared to controls, and the combination of ZOL and RT resulted in dissimilar
apoptosis between Abrams and D-17 and HMPOS
cell lines.
Cell cycle arrest (G2/
M phase) was minimal and variable between
cell lines but perhaps greatest at 48 h post-ZOL
treatment. Only 10% of
dogs treated with ZOL and RT developed
pathologic fractures, compared to 44% of
dogs historically treated with PAM and RT (p = 0.027).
Discussion:
ZOL and RT appear to be a well-tolerated combination
treatment scheme for non-surgical candidates;
future studies must elucidate the ideal timing of ZOL.
