Low-dose cyclophosphamide selectively decreases regulatory T cells and inhibits angiogenesis in dogs with soft tissue sarcoma

Jenna H Burton, L. Mitchell, D. H. Thamm, S. W. Dow, B. J. Biller

Research output: Contribution to journalArticle

67 Citations (Scopus)

Abstract

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 15mg/m 2 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 12.5mg/m 2/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 15.0mg/m 2/d, both the number and percent of Treg as well as tumor MVD were significantly decreased over 28 days. Conclusions: CYC administered at 15mg/m 2/d should be used in further studies examining the antitumor properties of low-dose CYC in dogs.

Original languageEnglish (US)
Pages (from-to)920-926
Number of pages7
JournalJournal of Veterinary Internal Medicine
Volume25
Issue number4
DOIs
StatePublished - Jul 2011
Externally publishedYes

Fingerprint

cyclophosphamide
sarcoma
Regulatory T-Lymphocytes
angiogenesis
Sarcoma
Cyclophosphamide
T-lymphocytes
Dogs
dogs
neoplasms
dosage
Microvessels
Neoplasms
drug therapy
Drug Therapy
tissues
T-Lymphocyte Subsets
flow cytometry
biopsy
clinical trials

Keywords

  • Cancer
  • Canine
  • Chemotherapy
  • Metronomic

ASJC Scopus subject areas

  • veterinary(all)

Cite this

Low-dose cyclophosphamide selectively decreases regulatory T cells and inhibits angiogenesis in dogs with soft tissue sarcoma. / Burton, Jenna H; Mitchell, L.; Thamm, D. H.; Dow, S. W.; Biller, B. J.

In: Journal of Veterinary Internal Medicine, Vol. 25, No. 4, 07.2011, p. 920-926.

Research output: Contribution to journalArticle

@article{2a9baf5cc8844d64a66040f89fb7e78c,
title = "Low-dose cyclophosphamide selectively decreases regulatory T cells and inhibits angiogenesis in dogs with soft tissue sarcoma",
abstract = "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 15mg/m 2 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 12.5mg/m 2/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 15.0mg/m 2/d, both the number and percent of Treg as well as tumor MVD were significantly decreased over 28 days. Conclusions: CYC administered at 15mg/m 2/d should be used in further studies examining the antitumor properties of low-dose CYC in dogs.",
keywords = "Cancer, Canine, Chemotherapy, Metronomic",
author = "Burton, {Jenna H} and L. Mitchell and Thamm, {D. H.} and Dow, {S. W.} and Biller, {B. J.}",
year = "2011",
month = "7",
doi = "10.1111/j.1939-1676.2011.0753.x",
language = "English (US)",
volume = "25",
pages = "920--926",
journal = "Journal of Veterinary Internal Medicine",
issn = "0891-6640",
publisher = "Wiley-Blackwell",
number = "4",

}

TY - JOUR

T1 - Low-dose cyclophosphamide selectively decreases regulatory T cells and inhibits angiogenesis in dogs with soft tissue sarcoma

AU - Burton, Jenna H

AU - Mitchell, L.

AU - Thamm, D. H.

AU - Dow, S. W.

AU - Biller, B. J.

PY - 2011/7

Y1 - 2011/7

N2 - 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 15mg/m 2 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 12.5mg/m 2/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 15.0mg/m 2/d, both the number and percent of Treg as well as tumor MVD were significantly decreased over 28 days. Conclusions: CYC administered at 15mg/m 2/d should be used in further studies examining the antitumor properties of low-dose CYC in dogs.

AB - 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 15mg/m 2 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 12.5mg/m 2/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 15.0mg/m 2/d, both the number and percent of Treg as well as tumor MVD were significantly decreased over 28 days. Conclusions: CYC administered at 15mg/m 2/d should be used in further studies examining the antitumor properties of low-dose CYC in dogs.

KW - Cancer

KW - Canine

KW - Chemotherapy

KW - Metronomic

UR - http://www.scopus.com/inward/record.url?scp=79960561470&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=79960561470&partnerID=8YFLogxK

U2 - 10.1111/j.1939-1676.2011.0753.x

DO - 10.1111/j.1939-1676.2011.0753.x

M3 - Article

VL - 25

SP - 920

EP - 926

JO - Journal of Veterinary Internal Medicine

JF - Journal of Veterinary Internal Medicine

SN - 0891-6640

IS - 4

ER -