Effects of late administration of pentoxifylline and tocotrienols in an image-guided rat model of localized heart irradiation

PLoS One. 2013 Jul 22;8(7):e68762. doi: 10.1371/journal.pone.0068762. Print 2013.

Abstract

Radiation-induced heart disease (RIHD) is a long-term side effect of radiotherapy of intrathoracic, chest wall and breast tumors when radiation fields encompass all or part of the heart. Previous studies have shown that pentoxifylline (PTX) in combination with α-tocopherol reduced manifestations of RIHD in rat models of local heart irradiation. The relative contribution of PTX and α-tocopherol to these beneficial effects are not known. This study examined the effects of PTX alone or in combination with tocotrienols, forms of vitamin E with potential potent radiation mitigation properties. Rats received localized X-irradiation of the heart with an image-guided irradiation technique. At 3 months after irradiation rats received oral treatment with vehicle, PTX, or PTX in combination with a tocotrienol-enriched formulation. At 6 months after irradiation, PTX-treated rats showed arrhythmia in 5 out of 14 animals. PTX alone or in combination with tocotrienols did not alter cardiac radiation fibrosis, left ventricular protein expression of the endothelial markers von Willebrand factor and neuregulin-1, or phosphorylation of the signal mediators Akt, Erk1/2, or PKCα. On the other hand, tocotrienols reduced cardiac numbers of mast cells and macrophages, but enhanced the expression of tissue factor. While this new rat model of localized heart irradiation does not support the use of PTX alone, the effects of tocotrienols on chronic manifestations of RIHD deserve further investigation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Administration, Oral
  • Animals
  • Antigens, CD / metabolism
  • Antigens, Differentiation, Myelomonocytic / metabolism
  • Cell Count
  • Drug Interactions
  • Endothelial Cells / cytology
  • Endothelial Cells / drug effects
  • Endothelial Cells / radiation effects
  • Heart / drug effects*
  • Heart / physiology
  • Heart / radiation effects*
  • Heart Ventricles / drug effects
  • Heart Ventricles / metabolism
  • Heart Ventricles / radiation effects
  • Male
  • Mast Cells / cytology
  • Mast Cells / drug effects
  • Mast Cells / radiation effects
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Models, Animal
  • Organs at Risk / radiation effects
  • Pentoxifylline / administration & dosage*
  • Pentoxifylline / pharmacology*
  • Phosphorylation / drug effects
  • Phosphorylation / radiation effects
  • Protein Kinase C-alpha / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Radiation Injuries / metabolism
  • Radiation Injuries / physiopathology
  • Radiation Injuries / prevention & control
  • Radiation-Protective Agents / administration & dosage
  • Radiation-Protective Agents / pharmacology
  • Radiotherapy, Image-Guided / adverse effects
  • Radiotherapy, Image-Guided / methods*
  • Rats
  • Rats, Sprague-Dawley
  • Tocotrienols / administration & dosage*
  • Tocotrienols / pharmacology*

Substances

  • Antigens, CD
  • Antigens, Differentiation, Myelomonocytic
  • CD68 antigen, human
  • Radiation-Protective Agents
  • Tocotrienols
  • Proto-Oncogene Proteins c-akt
  • Protein Kinase C-alpha
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Pentoxifylline