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Front. Vet. Sci. | doi: 10.3389/fvets.2018.00025

Metabolic Abnormalities Detected in Phase II Evaluation of Doxycycline in Dogs with Multicentric B-cell Lymphoma

 Kelly R. Hume1*, Skylar R. Sylvester2,  Lucia Borlle1, Cheryl E. Balkman1,  Angela L. McCleary-Wheeler1, Mary Pulvino3, Carla Casulo4 and Jiyong Zhao3, 4
  • 1Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, United States
  • 2College of Veterinary Medicine, Cornell University, United States
  • 3Department of Biomedical Genetics, University of Rochester Medical Center, United States
  • 4Wilmot Cancer Institute, University of Rochester Medical Center, United States

Doxycycline has anti-proliferative effects in human lymphoma cells and in murine xenografts. We hypothesized doxycycline would decrease canine lymphoma cell viability and prospectively evaluated its clinical tolerability in client-owned dogs with spontaneously-occurring, nodal, multicentric, substage a, B-cell lymphoma, not previously treated with chemotherapy. Treatment duration ranged from 1 – 8 weeks (median and mean, 3 weeks). Dogs were treated with either 10 mg/kg (n=6) or 7.5 mg/kg (n=7) by mouth twice daily. One dog had stable disease for 6 weeks. No complete or partial tumor responses were observed. Five dogs developed grade 3 and/or 4 metabolic abnormalities suggestive of hepatopathy with elevations in bilirubin, ALT, ALP, and/or AST. To evaluate absorption of oral doxycycline in our study population, serum concentrations in 10 treated dogs were determined using liquid chromatography tandem mass spectrometry. Serum levels were variable and ranged from 3.6 – 16.6 μg/ml (median, 7.6 μg/ml; mean, 8.8 μg/ml). To evaluate the effect of doxycycline on canine lymphoma cell viability in vitro, trypan blue exclusion assay was performed on canine B-cell lymphoma cell lines (17-71 and CLBL) and primary B-cell lymphoma cells from nodal tissue of 4 dogs. A doxycycline concentration of 6 μg/ml decreased canine lymphoma cell viability by 80%, compared to matched, untreated, control cells (mixed model analysis, p<0.0001; Wilcoxon signed rank test, p=0.0313). Although short term administration of oral doxycycline is not associated with remission of canine lymphoma, combination therapy may be worthwhile if future research determines that doxycycline can alter cell survival pathways in canine lymphoma cells. Due to the potential for metabolic abnormalities, close monitoring is recommended with use of this drug in tumor-bearing dogs. Additional research is needed to assess the tolerability of chronic doxycycline therapy.

Keywords: Dogs, hematopoietic neoplasm, tetracycline toxicity, Doxycycline, Lymphoma

Received: 24 Nov 2017; Accepted: 07 Feb 2018.

Edited by:

Bruno Cozzi, Università degli Studi di Padova, Italy

Reviewed by:

Robert Friis, University of Bern, Switzerland
Luca Aresu, Dipartimento di Scienze Veterinarie, Università degli Studi di Torino, Italy  

Copyright: © 2018 Hume, Sylvester, Borlle, Balkman, McCleary-Wheeler, Pulvino, Casulo and Zhao. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: DVM. Kelly R. Hume, Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, United States, krh73@cornell.edu