Evaluation of zoledronate for the treatment of canine stage III osteosarcoma: A phase II study

Smith, A.; Lindley, Stephanie E. S.; Almond, Greg; Bergman, Noelle; Matz, Brad M.; Smith, Annette

doi:10.1002/vms3.1000

Cited by 4 publications

(2 citation statements)

References 30 publications

(48 reference statements)

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“…Finally, ZOL’s use in the overt metastatic setting for dogs with pulmonary metastases from OS showed minimal efficacy in stage III disease. No azotemia was noted in a small cohort ( n = 8) of dogs evaluated at 1 month ( 29 ). The authors noted potential novel adverse events such as fever and conjunctivitis, but these clinical signs are well-documented and likely due to OS disease progression alone ( 30 ).…”

Section: Introductionmentioning

confidence: 98%

Effects of neoadjuvant zoledronate and radiation therapy on cell survival, cell cycle distribution, and clinical status in canine osteosarcoma

Norquest,

Rogic,

Gimotty

et al. 2024

Front. Vet. Sci.

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IntroductionZoledronic 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.MethodsWe 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).ResultsWe 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).DiscussionZOL and RT appear to be a well-tolerated combination treatment scheme for non-surgical candidates; future studies must elucidate the ideal timing of ZOL.

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Section: Introductionmentioning

confidence: 98%

Effects of neoadjuvant zoledronate and radiation therapy on cell survival, cell cycle distribution, and clinical status in canine osteosarcoma

Norquest,

Rogic,

Gimotty

et al. 2024

Front. Vet. Sci.

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“…However, the volume of metastatic tumors in the lungs increased in the group of mice that received zoledronate ( 16 ). Another study investigated the impact of zoledronate on stage III canine OSA patients and found that it did not extend the survival of these dogs with OSA ( 17 ).…”

Section: Introductionmentioning

confidence: 99%

An evaluation of the combination effect of zoledronate and chemotherapeutic agents in canine osteosarcoma cells

Iwaki,

Lindley,

Bergman

et al. 2024

Front. Vet. Sci.

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IntroductionOsteosarcoma (OSA) is an aggressive form of bone cancer in both dogs and humans. The treatment options for metastatic (stage III) OSA are currently limited and the prognosis is poor. Zoledronate, a second generation amino-bisphosphonate, is commonly used for palliation of cancer induced bone pain. Zoledronate has also demonstrated anti-cancer properties and possibly enhances the cytotoxicity of doxorubicin in a canine histiocytosis cell line and human prostatic cancer cell line. The goal of this study was to evaluate the combination effect of zoledronate and various chemotherapeutic drugs in canine OSA cells.MethodsCanine OSA cell line (D17), cells from two canine primary OSAs, and MDCK, a canine kidney cell line, were used to evaluate the therapeutic potential of these drugs. Carboplatin, doxorubicin, vinorelbine, toceranib, and isophosphoramide mustard (active metabolite of ifosfamide) were used as chemotherapeutic agents. First, cells were treated with either zoledronate or chemotherapy drug alone for 72 hours. Cell viability was assessed using CellTiter Glo and IC5, IC10, IC20, and IC50 were calculated. Second, cells were treated with a combination of zoledronate and each chemotherapeutic agent at their IC5, IC10, IC20, and IC50 concentrations. After 72 hours, cell viability was assessed by CellTiter Glo.Results and discussionZoledronate, carboplatin, doxorubicin, vinorelbine, and isophosphoramide mustard showed concentration dependent decrease in cell viability. Toceranib showed decreased cell viability only at higher concentrations. When zoledronate was used in combination with chemotherapy drugs, while it showed potential synergistic effects with toceranib, potential antagonistic effects with vinorelbine and isophosphoramide mustard were observed. However, the results differed by cell line and thus, further evaluation is warranted to understand the exact mechanism of action.

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Evaluation of zoledronate for the treatment of canine stage III osteosarcoma: A phase II study

Smith

Lindley

Almond

et al. 2022

Veterinary Medicine & Sci

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Background Greater than 90% of dogs with appendicular osteosarcoma will develop pulmonary metastasis despite the standard of care. Available treatments have limited efficacy for stage III disease. Zoledronate, a bisphosphonate, induces apoptosis of canine osteosarcoma cells and appears to modulate the tumour microenvironment. Objectives This prospective, single institutional phase IIa trial investigated the use of single agent zoledronate in dogs with pulmonary metastases from osteosarcoma. Methods Zoledronate was administered once monthly, and thoracic radiographs were used to assess response. Results Eleven dogs were enrolled. Stable disease was achieved in two of eight dogs available for response assessment. The median progression‐free survival was 28 days (range: 4–93 days). The median stage III‐specific survival time was 92 days. Adverse events were reported in four dogs; two dogs developed grade III or higher toxicities. Notable adverse events included conjunctivitis, fever, hypocalcaemia, and hypophosphatemia. Conclusions Zoledronate appears to have limited efficacy as a single agent for stage III osteosarcoma and may be associated with unexpected toxicity in this population. This clinical trial was registered on the AVMA Animal Health Studies Database (AAHSD004396).

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Evaluation of zoledronate for the treatment of canine stage III osteosarcoma: A phase II study

Cited by 4 publications

References 30 publications

Effects of neoadjuvant zoledronate and radiation therapy on cell survival, cell cycle distribution, and clinical status in canine osteosarcoma

Effects of neoadjuvant zoledronate and radiation therapy on cell survival, cell cycle distribution, and clinical status in canine osteosarcoma

An evaluation of the combination effect of zoledronate and chemotherapeutic agents in canine osteosarcoma cells

Evaluation of zoledronate for the treatment of canine stage III osteosarcoma: A phase II study

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