Prevention and Treatment of Functional and Structural Radiation Injury in the Rat Heart by Pentoxifylline and Alpha-Tocopherol

Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
International Journal of Radiation OncologyBiologyPhysics (Impact Factor: 4.26). 09/2008; 72(1):170-7. DOI: 10.1016/j.ijrobp.2008.04.042
Source: PubMed


Radiation-induced heart disease (RIHD) is a severe side effect of thoracic radiotherapy. This study examined the effects of pentoxifylline (PTX) and alpha-tocopherol on cardiac injury in a rat model of RIHD.
Male Sprague-Dawley rats received fractionated local heart irradiation with a daily dose of 9 Gy for 5 days and were observed for 6 months after irradiation. Rats were treated with a combination of PTX, 100 mg/kg/day, and alpha-tocopherol (20 IU/kg/day) and received these compounds either from 1 week before until 6 months after irradiation or starting 3 months after irradiation, a time point at which histopathologic changes become apparent in our model of RIHD.
Radiation-induced increases in left ventricular diastolic pressure (in mm Hg: 35 +/- 6 after sham-irradiation, 82 +/- 11 after irradiation) were significantly reduced by PTX and alpha-tocopherol (early treatment: 48 +/- 7; late treatment: 53 +/- 6). PTX and alpha-tocopherol significantly reduced deposition of collagen types I (radiation only: 3.5 +/- 0.2 mum(2) per 100 mum(2); early treatment: 2.7 +/- 0.8; late treatment: 2.2 +/- 0.2) and III (radiation only: 13.9 +/- 0.8; early treatment: 11.0 +/- 1.2; late treatment: 10.6 +/- 0.8). On the other hand, radiation-induced alterations in heart/body weight ratios, myocardial degeneration, left ventricular mast cell densities, and most echocardiographic parameters were not significantly altered by PTX and alpha-tocopherol.
Treatment with PTX and alpha-tocopherol may have beneficial effects on radiation-induced myocardial fibrosis and left ventricular function, both when started before irradiation and when started later during the process of RIHD.

Download full-text


Available from: Martin Hauer-Jensen, Jul 30, 2014
    • "Because in our previous studies a single dose of 18 Gy caused only mild eff ects in the heart, and a single dose of 24 Gy is generally considered a high dose in animal models of local heart irradiation, we here elected to use an intermediate radiation dose of 21 Gy. We have previously shown that it produces moderate cardiac radiation injury in the rat, similar to fractionated schedules as also used in our laboratory (Boerma et al. 2008). Th e best-described B2 receptor antagonist, HOE-140, has been used in many animal models, and has even reached clinical use to relieve acute swelling attacks in hereditary angioedema patients (Bork et al. 2007). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Radiation-induced heart disease (RIHD) is a delayed effect of radiotherapy for cancers of the chest, such as breast, esophageal, and lung. Kinins are small peptides with cardioprotective properties. We previously used a rat model that lacks the precursor kininogen to demonstrate that kinins are involved in RIHD. Here, we examined the role of the kinin B2 receptor (B2R) in early radiation-induced signaling in the heart. Male Brown Norway rats received the B2R-selective antagonist HOE-140 (icatibant) via osmotic minipump from 5 days before until 4 weeks after 21 Gy local heart irradiation. At 4 weeks, signaling events were measured in left ventricular homogenates and nuclear extracts using western blotting and real-time polymerase chain reaction. Numbers of CD68-positive (monocytes/macrophages), CD2-positive (T-lymphocytes), and mast cells were measured using immunohistochemistry. Radiation-induced c-Jun phosphorylation and nuclear translocation were enhanced by HOE-140. HOE-140 did not modify endothelial nitric oxide synthase (eNOS) phosphorylation or alter numbers of CD2-positive or mast cells, but enhanced CD68-positive cell counts in irradiated hearts. B2R signaling may regulate monocyte/macrophage infiltration and c-Jun signals in the irradiated heart. Although eNOS is a main target for kinins, the B2R may not regulate eNOS phosphorylation in response to radiation.
    No preview · Article · May 2015 · International Journal of Radiation Biology
  • Source
    • "Radiation-induced vascular injury and endothelial dysfunction are mediated in part by TGF-b1 [13], a pluripotent growth factor that is part of many normal tissue radiation responses [14] [15]. Previous studies have shown upregulation of TGF-b1 in rat models with radiation induced damage after localized heart irradiation with 20 Gy or 5 fractions of 9 Gy [16]. Cardiac radiation fibrosis is more severe in animals that have been administered the TGF-b1 inducing compound during the 6-month follow-up time after irradiation, and pre-clinical studies involving TGFreceptor inhibition are being undertaken [17]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The Growth Differentiation Factor-15 gene (GDF15) is a member of TGF-b superfamily and this cytokine family is considered to be a promising target for cancer therapy. The purpose of this study was to investigate the effect of tumor derived GDF15 on proliferation and radiosensitivity of breast cancer cells in vitro and in vivo. A mouse breast cancer LM2 cell line with stable transfection of full-length mouse GDF15 cDNA was established. Cell growth and proliferation was observed using WST assay and impedance-based method. Radiation induced GDF15 and TGF-b1 expression was determined by qRT-PCR. Radiosensitivity was measured by a colony formation assay in vitro and by a tumor growth delay assay in vivo. Cells with more than a 10-fold increase in GDF15 expression had a higher growth rate than parental control cells in vitro and in vivo. The radiation induced elevation of the expression of TGFb1 was reduced in GDF15 overexpressing cells. GDF15 may play a role in the radiation response of breast cancer cells by effecting cell survival, inhibiting radiation-induced cell death, and inhibiting the TGF-b1 related cytotoxic action.
    Full-text · Article · Oct 2014 · Central European Journal of Biology
  • Source
    • "Previous studies have shown that PTX improved cardiac function and reduced adverse remodeling when administered in combination with α-tocopherol after local heart irradiation in rats [16,17]. In our previous studies, PTX was administered at 100 mg/kg bodyweight/day in combination with α-tocopherol at 40 mg/kg body weight/day [16]. "
    [Show abstract] [Hide abstract]
    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.
    Full-text · Article · Jul 2013 · PLoS ONE
Show more