Low-Dose Cyclophosphamide Selectively Decreases Regulatory T Cells and Inhibits Angiogenesis in Dogs with Soft Tissue Sarcoma

• Published in: Journal of veterinary internal medicine Vol. 25; no. 4; pp. 920 - 926
• Main Authors: Burton, J.H., Mitchell, L., Thamm, D.H., Dow, S.W., Biller, B.J.
• Format: Journal Article
• Language: English
• Published: Malden, USA Blackwell Publishing Inc 01-07-2011
• Subjects: Animals; Antineoplastic Agents - administration & dosage; Biopsy - veterinary; Cancer; Canine; Chemotherapy; Cohort Studies; Cyclophosphamide - administration & dosage; Dog Diseases - drug therapy; Dog Diseases - immunology; Dog Diseases - pathology; Dogs; Dose-Response Relationship, Drug; Flow Cytometry - veterinary; Immunophenotyping - veterinary; Metronomic; Neovascularization, Pathologic - drug therapy; Neovascularization, Pathologic - pathology; Neovascularization, Pathologic - veterinary; Pilot Projects; Prospective Studies; Quality of Life; Sarcoma - blood supply; Sarcoma - drug therapy; Sarcoma - immunology; Sarcoma - veterinary; Soft Tissue Neoplasms - blood supply; Soft Tissue Neoplasms - drug therapy; Soft Tissue Neoplasms - immunology; Soft Tissue Neoplasms - veterinary; T-Lymphocytes, Regulatory - drug effects
• ISSN: 0891-6640; 1939-1676
• DOI: 10.1111/j.1939-1676.2011.0753.x

Background: Low‐dose, continuous (metronomic) chemotherapy improves tumor control by inhibiting tumor angiogenesis and suppressing regulatory T cells (Treg) in mice and humans. The effects of metronomic chemotherapy on Treg and tumor angiogenesis in dogs has not been investigated previously.
Objective: To determine whether metronomic cyclophosphamide (CYC) therapy decreases Treg or exhibits antiangiogenic activity or both in dogs with soft tissue sarcoma (STS). We hypothesized that Treg numbers would be increased in dogs with STS and that continuous dosing of CYC would decrease Treg in a dose‐dependent manner, as well as exhibit antiangiogenic activity.
Animals: Eleven client‐owned dogs with grade I or II STS. Twenty‐one healthy dogs were used as controls.
Methods: Prospective, open, clinical trial. Dogs with STS were enrolled in 2 dose cohorts and administered CYC at 12.5 or 15 mg/m2 PO once daily for 28 days. Whole blood and tumor biopsy specimens were obtained on days 0, 14, and 28 to assess changes in T lymphocyte subsets by flow cytometry and tumor microvessel density (MVD), respectively.
Results: Administration of CYC at 12.5 mg/m2/d significantly decreased the number of Treg from days 0 to 28, but there was no change in the percentage of Treg or tumor MVD. In dogs that received CYC at 15.0 mg/m2/d, both the number and percent of Treg as well as tumor MVD were significantly decreased over 28 days.
Conclusions: CYC administered at 15 mg/m2/d should be used in further studies examining the antitumor properties of low‐dose CYC in dogs.