Purpose-Osteosarcoma (OS) remains an incurable and ultimately fatal disease in many patients, and novel forms of therapy are needed. Improved models of OS that more closely mimic human disease would provide more robust information regarding the utility of novel therapies. Spontaneous OS in dogs may provide such a model. Pharmacologic inhibition of histone deacetylase (HDAC) enzymes has a variety of anti-tumor effects but may demonstrate the most utility when utilized in combination with standard cytotoxic therapies. We sought to determine the in vitro and in vivo effects of the HDAC inhibitor valproic acid (VPA) on doxorubicin (DOX) sensitivity in canine and human OS. NIH Public AccessAuthor Manuscript Cancer Chemother Pharmacol. Author manuscript; available in PMC 2012 January 1. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptMethods-We evaluated the in vitro anti-proliferative and apoptotic effects of VPA/DOX combination treatment, alterations in histone acetylation and nuclear DOX accumulation resulting from VPA treatment, and the in vivo efficacy of combination therapy in a xenograft model.Results-Treatment of canine and human OS cell lines with clinically achievable VPA concentrations resulted in increased histone acetylation but modest anti-proliferative effects. Preincubation with VPA followed by doxorubicin (DOX) resulted in significant growth inhibition and potentiation of apoptosis, associated with a dose-dependent increase in nuclear DOX accumulation. The combination of VPA and DOX was superior to either monotherapy in a canine OS xenograft model.Conclusion-These results demonstrate a rationale for the addition of HDAC inhibitors to current protocols for the treatment of OS and illustrate the similarities in response to HDAC inhibitors between human and canine OS, lending further credibility to the canine OS model.
Objectives Measure drug exposure and clinic effects after administration of transdermal mirtazapine (TMZ) in healthy cats. Methods Phase I: Seven healthy research cats received A) 3.75 mg and 7.5 mg TMZ once aurally with 48 hour serum sampling (serum samples were obtained via jugular catheter at 0, 0.5, 1, 2, 5, 9, 12, 24, 36 and 48 h), B) 7.5 mg TMZ and placebo daily aurally for six days then 48 h serum sampling C) 1.88 mg mirtazapine orally once with serum sampling at 1, 4 and 8 h. Phase II: Twenty client-owned cats were enrolled in a randomized double-blind placebo-controlled three-way crossover clinical effect study. Treatments consisted of six days of aural 7.5 mg TMZ or placebo gel at home, and 1.88 mg mirtazapine orally once in clinic. Owners documented appetite, rate of food ingestion, begging, activity and vocalization daily at home. On day six, food consumed, activity and vocalization were documented in hospital and trough and peak serum mirtazapine levels obtained. Serum mirtazapine and gel concentrations were measured using liquid chromatography/tandem mass spectrometry. Results Phase I: Administration of TMZ achieved measureable serum mirtazapine concentrations. AUC0-48 of multidose 7.5 mg TMZ was significantly higher than single dose 1.88 mg OMZ (P = 0.02). Phase II: Client-owned cats administered TMZ had a significant increase in appetite (P = 0.003), rate of food ingestion (P = 0.002), activity (P = 0.002), begging (P = 0.002) and vocalization (P = 0.002) at home. In hospital there was a significant increase in food ingested with both TMZ and OMZ compared to placebo (P < 0.05). Gel concentrations ranged from 87%–119% of target dose. Conclusions and relevance 7.5 mg daily TMZ achieves measureable serum concentrations and significant appetite stimulation despite variance in compounded gel concentrations, but side effects denote a lower dose is indicated.
Osteosarcoma (OSA) represents the most common primary bone tumor in humans and pet dogs. Little progress has been made with regard to viable treatment options in the past three decades and patients presenting with metastatic disease continue to have a poor prognosis. Recent mouse studies have suggested that microRNA-34a (miR-34a) may have anti-tumor activities in human OSA models. Due to the conservation of microRNA across species, we hypothesized that a bioengineered miR-34a prodrug (tRNA/miR-34a) would have similar effects in canine OSA, providing a valuable preclinical model for development of this therapeutic modality. Using a panel of canine OSA cell lines, we found that tRNA/miR-34a reduced viability, clonogenic growth, and migration and invasion while increasing tumor cell apoptosis. Furthermore, canine OSA cells successfully process the tRNA/miR-34a into mature miR-34a which reduces expression of target proteins such as platelet derived growth factor receptor alpha (PDGFRα), Notch1 and vascular endothelial growth factor (VEGF). Additionally, our subcutaneous OSA xenograft model demonstrated in vivo tumor growth delay, increased necrosis and apoptosis by tRNA/miR-34a, and decreased cellular proliferation ability. Taken together, these data support that this novel microRNA-based therapy may possess clinical utility in a spontaneously-occurring large animal model of OSA, which can then serve to inform the clinical development of this therapy for human OSA patients.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.