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: 4.18). 09/2008; 72(1):170-7. DOI: 10.1016/j.ijrobp.2008.04.042
Source: PubMed

ABSTRACT 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
  • 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.
    Central European Journal of Biology 10/2014; 9(10). DOI:10.2478/s11535-014-0328-8 · 0.63 Impact Factor
  • 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.
    PLoS ONE 07/2013; 8(7):e68762. DOI:10.1371/journal.pone.0068762 · 3.23 Impact Factor
  • Source
    • "for at least 6 months has proven to be a safe and effective antifibrotic treatment in experimental animal models [6] [7] and in clinical practice. Several phase II and III clinical trials conducted by Delanian et al. [8] [9] [10] [11] [12] and confirmed by other groups [13] [14] have reported the efficacy of pentoxifylline–vitamin E. Despite these successful clinical trials, researchers have not yet been able to show consistently that using either pentoxifylline or vitamin E alone can significantly reduce radiation fibrosis and little is known about the molecular mechanism involved in this clinical anti-fibrotic action of pentoxifylline–vitamin E [15]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND: Radiation-induced fibrosis is a serious late complication of radiotherapy. Pentoxifylline-vitamin E has proven effective and safe in clinical trials in the treatment of fibrosis, while the molecular mechanism of its activity is yet unexplored. METHODS: Ten patients suffering from radiation-induced enteropathy were treated with pentoxifylline-vitamin E combination with SOMA score as the primary endpoint. In parallel, primary smooth muscle cells isolated from intestinal samples isolated from humans with radiation enteropathy were incubated with pentoxifylline, trolox (vit. E hydrophilic analogous) or their combination. Activation of the TGF-β1/Smad and Rho/ROCK pathways was subsequently investigated using Q-RT-PCR, gene reporter, Western-blot, ELISA and immunohistochemistry. RESULTS: Pentoxifylline-vitamin E combination induces regression of symptoms (SOMA) by -41% and -80% at 6 and 18months. In vitro, pentoxifylline and trolox synergize to inhibit TGF-β1 protein and mRNA expression. This inhibitory action is mediated at the transcriptional level and leads to subsequent inhibition of TGF-β1/Smad targets (Col Iα1, FN1, PAI-1, CTGF), while it has no effect on the Rho/ROCK pathway. CONCLUSIONS: The anti-fibrotic effect of combined pentoxifylline-vitamin E is at least in part mediated by inhibition of the TGF-β1 cascade. It strengthens previous clinical data showing pentoxifylline-vitamin E synergy and supports its use as a first-line treatment of radiation-induced fibrosis.
    Radiotherapy and Oncology 09/2012; 105(3). DOI:10.1016/j.radonc.2012.08.023 · 4.86 Impact Factor
Show more