Systemic administration of heparin ameliorates radiation-induced oral mucositis—preclinical studies in mice
Tóm tắt
The present study investigates the impact of systemic application of heparins on the manifestation of radiation-induced oral mucositis in a well-established mouse model. Male C3H/Neu mice were irradiated with either single-dose or fractionated irradiation protocols with 5 × 3 Gy/week, given over one (days 0–4) or two (days 0–4, 7–11) weeks. All fractionation protocols were concluded by a local test irradiation (day 7/14) using graded doses to generate complete dose–effect curves. Daily doses of unfractionated or low molecular weight heparin (40 or 200 I.U./mouse, respectively) were applied subcutaneously over varying time intervals. The incidence and the time course of mucosal ulceration, corresponding to confluent mucositis in patients (RTOG/EORTC grade 3), were analysed as clinically relevant endpoints. Systemic application of heparins significantly increased the iso-effective doses for the induction of mucosal ulceration, particularly in combination with fractionated irradiation protocols. Moreover, a tentative prolongation of the latent time and a pronounced reduction of the ulcer duration were observed. These data provide the first evidence for a protective and/or mitigative effect of heparins for radiation-induced oral mucositis. Further studies are ongoing investigating the underlying mechanism.
Tài liệu tham khảo
Sonis ST (2004) Pathobiology of mucositis. Semin Oncol Nurs 20:11–15
Viet CT, Corby PM, Akinwande A, Schmidt BL (2014) Review of preclinical studies on treatment of mucositis and associated pain. J Dent Res 93:868–875
Sonis ST (2012) Pathobiology of oral mucositis: novel insights and opportunities. J Support Oncol 5:7–13
Oduah E, Linhardt R, Sharfstein S (2016) Heparin: past, present, and future. Pharmaceuticals (Basel) 9:38
Page C (2013) Heparin and related drugs: beyond anticoagulant activity. ISRN Pharmacol 2013:13
Dörr W, Spekl K, Farrell CL (2002) Amelioration of acute oral mucositis by keratinocyte growth factor: fractionated irradiation. Int J Radiat Oncol Biol Phys 54:245–251
Dörr W, Herrmann T, Reitemeier B et al (2008) Folgen der Strahlentherapie in der Mundhöhle. Zahnmed Up2date 6:543–569
Dörr W, Spekl K, Martin M (2002) Radiation-induced oral mucositis in mice : strain differences. Cell Prolif 35:60–67
Casu B, Vlodavsky I, Sanderson RD (2008) Non-anticoagulant heparins and inhibition of cancer. Pathophysiol Haemost Thromb 36:195–203
Dörr W, Herrmann T, Trott K (2017) Normal tissue tolerance. Transl Cancer Res 6:840–851
Thourani VH, Brar SS, Kennedy TP et al (2000) Non-anticoagulant heparin inhibits NF-κ B activation and attenuates myocardial reperfusion injury. Am J Physiol Heart Circ Physiol 48:2084–2093
Lee JH, Lee J, Seo GH (2007) Heparin inhibits NF- κ B activation and increases cell death in cerebral endothelial cells after oxygen-glucose deprivation. J Mol Neurosci 32:145–154
Spratte J, Meyer H, Endlich N et al (2013) Heparin inhibits TNF- a signaling in human endometrial stromal cells by interaction with NF- k B. Mol Hum Reprod 19:227–236
Al-Ansari S, Zecha JAEM, Barasch A et al (2015) Oral mucositis induced by anticancer therapies. Curr Oral Health Rep 2:202–211
Grzela T, Brawura-Biskupski-Samaha R, Jelenska MM, Szmidt J (2008) Low molecular weight heparin treatment decreases MMP-9 plasma activity in patients with abdominal aortic aneurysm. Eur J Vasc Endovasc Surg 35:159–161
D’Hondt L, Lonchay C, André M, Canon JL (2006) Oral mucositis induced by anticancer treatments: physiopathology and treatments. Ther Clin Risk Manag 2:159–168
Kim PJ, Sakaguchi K, Sakamoto H et al (1998) Colocalization of heparin and receptor binding sites on keratinocyte growth factor. Biochemistry 37:8853–8862
Jaal J, Richter C, Dörr W (2010) Effect of recombinant human keratinocyte growth factor ( Delta 23rHuKGF, Palifermin ) on inflammatory and immune changes in mouse tongue during fractionated irradiation. Int J Radiat Biol 86:860–866
Hallahan DE, Subbulakshmi V (1997) Intercellular adhesion molecule 1 knockout abrogates radiation. Proc Natl Acad Sci Usa 94:6432–6437
Quaranta M, Erez O, Mastrolia SA et al (2015) The physiologic and therapeutic role of heparin in implantation and placentation. PeerJ 3:e691
Dörr W (1997) Strahlenbiologische Parameter der radiogenen Mucositis enoralis. Habilitation manuscript