Amifostine is well known cytoprotector which is efficient when administered before a wide range of antineoplastic agents. The aim of our study was to investigate amifostine effects on doxorubicin-induced toxic changes in rats. Amifostine (75 mg/kg ip) was given 30 min before each dose of doxorubicin (cumulatively 20 mg/kg ip, for 28 days). The animals' whole-body, liver, and kidney weight, serum biochemical examination, as well as microscopic examination of bone marrow, peripheral blood, liver, and kidney, were done on day 56 of the study. Hepatic and renal alterations were carefully quantified by semiquantitative grading scales-hepatic and renal damage score, respectively. In amifostine-pretreated rats, the number of peripheral blood leukocytes was significantly higher in comparison to doxorubicin-only treated group, preferentially protecting neutrophils. In the same group of rats, hepatic and renal alterations associated with polymorphonuclear cell infiltrates were significantly less severe than those observed in animals receiving only doxorubicin. Our results showed that amifostine successfully protected rats against multiple-dose doxorubicin-induced toxicity by complex, and still not fully elucidated mechanisms of action.

Centre for Clinical Pharmacology Military Medical Academy 11 Crnotravska St 11000 Belgrade Serbia

Department of Chemistry Faculty of Science University of Hradec Kralove Rokitanského 62 50003 Hradec Králové Czech Republic

Department of Experimental Toxicology and Pharmacology National Poison Control Centre Military Medical Academy 11 Crnotravska St 11000 Belgrade Serbia

Department of Neurology Charles University Prague Faculty of Medicine in Hradec Kralove and University Hospital Simkova 870 50003 Hradec Králové Czech Republic

Institute for Pathology Military Medical Academy 11 Crnotravska St 11000 Belgrade Serbia

Institute for Scientific Information University of Defense in Belgrade 1 Pavla Jurišića Šturma St 11000 Belgrade Serbia

Medical Faculty of the Military Medical Academy University of Defense in Belgrade 1 Pavla Jurišića Šturma St 11000 Belgrade Serbia

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Bonadonna G., Valagudda P. Primary Chemotherapy in Operable Breast Cancer. Semin. Oncol. 1998;23:464–474. doi: 10.1200/JCO.1998.16.1.93. PubMed DOI

Dollery C. Cyclophosphamide. In: Dollery C., editor. Therapeutic Drugs. 2nd ed. Churchill Livingstone; Edinburgh, UK: 1999. pp. 349–354. ISBN-10: 0443051488, ISBN-13: 978-0443051487.

Hortobagyi G.N. Anthracyclines in the Treatment of Cancer. An Overview. Drugs. 1997;54:1–7. doi: 10.2165/00003495-199700544-00003. PubMed DOI

Gewitz D.A. A Critical Evaluation of the Mechanisms of Action Proposed for the Antitumor Effects of the Anthracycline Antibiotics Adriamycin and Daunorubicin. Biochem. Pharmacol. 1999;57:727–741. doi: 10.1016/S0006-2952(98)00307-4. PubMed DOI

Minoti G., Menna P., Salvatorelli E., Cairo G., Gianni L. Anthracyclines: Molecular Advances and Pharmacologic Development in Antitumor Activity and Cardiotoxicity. Pharmacol. Rev. 2004;56:185–229. doi: 10.1124/pr.56.2.6. PubMed DOI

Mross K. New Anthracycline Derivates: What for? Eur. J. Cancer Clin. Oncol. 1991;27:1542–1544. doi: 10.1016/0277-5379(91)90409-7. PubMed DOI

Sayed-Ahmed M.M., Al-Shabanah O.A., Hafez M.M., Aleisa A.M., Al-Rejaie S.S. Inhibition of Gene Expression of Heart Fatty Acid Binding Protein and Organic Cation/Carnitine Transporter in Doxorubicin Cardiomyopathic Rat Model. Eur. J. Pharmacol. 2010;640:143–149. doi: 10.1016/j.ejphar.2010.05.002. PubMed DOI

Martindale . The Complete Drug Reference [CD-ROM] 36th ed. Pharmaceutical Press; London, UK: 2011. ISBN-13: 978-0853698425, ISBN-10: 0853698422.

Saad Y.S., Najjar A.T., Al-Rikabi A.C. The Preventive Role of Deferoxamine against Acute Doxorubicin Induced Cardiac, Renal and Hepatic Toxicity in Rats. Pharmacol. Res. 2000;43:211–218. doi: 10.1006/phrs.2000.0769. PubMed DOI

Mihailović-Stanojević N., Jovović D., Miloradović Z., Grujić-Milovanović J., Marković-Lipovski J. Reduced Progression of Adriamycin Nephropathy in Spontaneously Hypertensive Rats Treated by Losartan. Nephrol. Dial. Transplant. 2009;24:1142–1150. doi: 10.1093/ndt/gfn596. PubMed DOI

Roomi M.W., Kalinovsky T., Roomi N.W., Rath M., Niedzwiecki A. Prevention of Adriamycin-Induced Hepatic and Renal Toxicity in Male BALB/c Mice by a Nutrient Mixture. Exp. Ther. Med. 2014;7:1040–1044. doi: 10.3892/etm.2014.1535. PubMed DOI PMC

Dragojević-Simić V., Dobrić S., Jaćević V., Bokonjić D., Milosavljević I., Kovačević A., Mikić D. Efficacy of amifostine in protection against doxorubicin-induced acute cardiotoxic effects in rats. Vojnosanit. Pregl. 2013;70:38–45. doi: 10.2298/VSP110905041D. PubMed DOI

Herman E.H., Zhang J., Chadwick D.P., Ferrans V.J. Comparison of the Protective Effects of Amifostine and Dexrazoxane against the Toxicity of Doxorubicin in Spontaneously Hypertensive Rats. Cancer Chemother. Pharmacol. 2000;45:329–334. doi: 10.1007/s002800050048. PubMed DOI

Okunewick J.P., Buffo M.J., Kociban D.L. Comparative Toxicity of Mitoxantrone and Doxorubicin on Hematopoietic Stem Cells. Exp. Hematol. 1985;13:23–30. PubMed

Pugazhendhi A., Jebakumar T.N., Edison I., Velmurugan B.K., Jacob J.A., Karuppusamy I. Toxicity of Doxorubicin (Dox) to Different Experimental Organ Systems. Life Sci. 2018;200:26–30. doi: 10.1016/j.lfs.2018.03.023. PubMed DOI

Octavia Y., Tocchetti C.G., Gabrielson K.L., Janssens S., Crijns H.J., Moens A.L. Doxorubicin-induced cardiomyopathy: From molecular mechanisms to therapeutic strategies. J. Mol. Cell. Cardiol. 2012;52:1213–1225. doi: 10.1016/j.yjmcc.2012.03.006. PubMed DOI

El-Sayyad H.I., Ismail M.F., Shalaby F.M., Abou-El-Magd R.F., Gaur R.L., Fernando A., Raj M.H.G., Ouhtit A. Histopathological effects of cisplatin, doxorubicin and 5-flurouracil (5-FU) on the liver of male albino rats. Int. J. Biol. Sci. 2009;5:466–473. doi: 10.7150/ijbs.5.466. PubMed DOI PMC

Ayla S., Seckin I., Tanriverdi G., Cengiz M., Eser M., Soner B.C., Oktem G. Doxorubicin induced nephrotoxicity: Protective effect of nicotinamide. Int. J. Cell Biol. 2011;2011:390238. doi: 10.1155/2011/390238. PubMed DOI PMC

Lahoti T.S., Patel D., Thekkemadom V., Beckett R., Ray S.D. Doxorubicin-induced in vivo nephrotoxicity involves oxidative stress-mediated multiple pro- and anti-apoptotic signaling pathways. Curr. Neurovasc. Res. 2012;9:282–295. doi: 10.2174/156720212803530636. PubMed DOI

Camaggi C.M., Comparsi R., Srtocchi E., Testoni F., Angelelli B., Pannuti F. Epirubicin and Doxorubicin Comparative Metabolism and Pharmacokinetics. Cancer Chemother. Pharmacol. 1988;21:221–228. doi: 10.1007/BF00262774. PubMed DOI

Ganey P.E., Kauffman F.C., Thurman R.G. Oxigen Dependent Hepatotoxicity Due to Doxorubicin: Role of Reducing Equivalent Supply in Perfused Rat Liver. Mol. Pharmacol. 1988;34:695–701. PubMed

Ballet F., Vrignaud P., Robert J., Rey C., Poupon R. Hepatic Extraction, Metabolism and Biliary Excretion of Doxorubicin in the Isolated Perfused Rat Liver. Cancer Chemother. Pharmacol. 1987;19:240–245. doi: 10.1007/BF00252979. PubMed DOI

Dodion P., Bernstein A.L., Fox B.M., Bachur N.R. Loss of Fluorescence by Anthracycline Antibiotics: Effects of Xanthine Oxidase and Identification of the Nonfluorescent Metabolites. Cancer Res. 1987;47:1036–1039. PubMed

Aryal B., Jeong J., Rao V.A. Doxorubicin-Induced Carbonylation of Cardiac Myosin Binding Protein C Promote Cardiotoxicity. Proc. Natl. Acad. Sci. USA. 2014;111:2011–2016. doi: 10.1073/pnas.1321783111. PubMed DOI PMC

Sung C.C., Hsu Y.C., Chen C.C., Lin Y.F., Wu C.C. Oxidative Stress and Nucleic Acid Oxidation in Patients with Chronic Kidney Disease. Oxid. Med. Cell. Longev. 2013;2013:301982. doi: 10.1155/2013/301982. PubMed DOI PMC

Karanovic D., Grujic-Milanovic J., Miloradovic Z., Ivanov M., Jovovic D.J., Vajic U.J., Zivotic M., Markovic-Lipkovski J., Mihailovic-Stanojevic N. Effects of Single and Combined Losartan and Tempol Treatments on Oxidative Stress, Kidney Structure and Function in Spontaneously Hypertensive Rats with Early Course of Proteinuric Nephropathy. PLoS ONE. 2016;11:e0161706. doi: 10.1371/journal.pone.0161706. PubMed DOI PMC

Jovanović D.B., Jovović D., Varagić J., Dimitrijević J., Dragojlović Z., Djukanović L. Slowing Progression of Chronic Renal Insufficiency with Captopril in Rats with Spontaneous Arterial Hypertension and Adriamycin Nephropathy. Srp. Arh. Celok. Lek. 2002;130:73–80. doi: 10.2298/SARH0204073J. PubMed DOI

Alshabanah O.A., Hafez M.M., Al-Harbi M.M., Hassan Z.K., Al Rejaie S.S., Asiri Y.A., Sayed-Ahmed M.M. Doxorubicin Toxicity Can be Ameliorated during Antioxidant L-Carnitine Supplementation. Oxid. Med. Cell. Longev. 2014;2:428–433. doi: 10.4161/oxim.3.6.14416. PubMed DOI PMC

Dragojevic-Simic V., Jacevic V., Dobric S., Djordjevic A., Bokonjic D., Bajcetic M., Injac R. Anti-Inflammatory Activity of Fullerenol C60(OH)24 Nano-Particles in a Model of Acute Inflammation in Rats. Dig. J. Nanomater. Biostruct. 2011;6:819–827.

Dorr R.T., Holmes B.C. Dosing considerations with amifostine: A Review of the Literature and Clinical Experience. Semin. Oncol. 1999;26:108–119. PubMed

Sterba M., Popelova O., Vavrova A., Jirkovsky E., Kovaríkova P., Gersl V., Simunek T. Oxidative Stress, Redox Signaling, and Metal Chelation in Anthracycline Cardiotoxicity and Pharmacological Cardioprotection. Antioxid. Redox Signal. 2013;18:899–929. doi: 10.1089/ars.2012.4795. PubMed DOI PMC

Jacevic V., Djordjevic A., Srdjenovic B., Milic-Tores V., Segrt Z., Dragojevic-Simic V., Kuca K. Fullerenol Nanoparticles Prevents Doxorubicin-Induced Acute Hepatotoxicity in Rats. Exp. Mol. Pathol. 2017;102:360–369. doi: 10.1016/j.yexmp.2017.03.005. PubMed DOI

Dragojevic-Simic V.M., Dobric S.L., Bokonjic D.R., Vucinic Z.M., Sinovec S.M., Jacevic V.M., Dogovic N.P. Amifostine Protection against Doxorubicin Cardiotoxicity in Rats. Anti Cancer Drugs. 2004;15:169–178. doi: 10.1097/00001813-200402000-00011. PubMed DOI

Spencer C.M., Goa K.L. Amifostine: A review of Its Pharmacodynamic and Pharmacokinetic Properties, and Therapeutic Potential as a Radioprotector and Cytotoxic Chemoprotector. Drugs. 1995;50:1001–1031. doi: 10.2165/00003495-199550060-00008. PubMed DOI

Capizzi R.L. The Preclinical Basis for Broad-Spectrum Selective Cytoprotection of Normal Tissue from Cytotoxic Therapies by Amifostine. Semin. Oncol. 1999;26:3–21. doi: 10.1016/S0959-8049(96)00333-4. PubMed DOI

Kouvaris J., Kouloullas V., Vlahos L. Amifostine: The First Selective-Target and Broad-Spectrum Radioprotector. Oncology. 2007;12:738–747. doi: 10.1634/theoncologist.12-6-738. PubMed DOI

Kligerman M.M., Turrisi A.T., Urtasun R.C., Norfleet A.L., Phillips T.L., Barkley T., Rubin P. Final Report On Phase I Trial of WR-2721 before Protracted Fractionated Radiation Therapy. Int. J. Radiat. Oncol. Biol. Phys. 1988;14:1119–1122. doi: 10.1016/0360-3016(88)90387-2. PubMed DOI

Wasserman T.H., Phillips T.L., Ross G., Kane L.J. Differential Protection against Cytotoxic Chemotherapeutic Effects on Bone Marrow CFUs by WR-2721. Cancer Clin. Trial. 1981;4:3–6. PubMed

Shpall E.J., Stemmer S.M., Hami L., Franklin W.A., Shaw L., Bonner H.S., Bearman S.I., Peters W.P., Bast R.C., McCulloch W. Amifostine (WR-2721) Shortens the Engraftment Period of 4-hydroperoxy-Cyclophosphamide-Purged Bone Marrow in Breast Cancer Patients Receiving High-Dose Chemotherapy with Autologous Bone Marrow Support. Blood. 1994;83:3132–3137. PubMed

Rossi F., Filipelli W., Russo S., Filippelli A., Berrino L. Cardiotoxicity of Doxorubicin: Effects of Drugs Inhibiting the Release of Vasoactive Substances. Pharmacol. Toxicol. 1994;75:99–107. doi: 10.1111/j.1600-0773.1994.tb00330.x. PubMed DOI

Herman E.H., Zhang J., Ferrans V. Comparison of the Protective Effects of Desferrioxamine and ICRF-187 against Doxorubicin-Induced Toxicity in Spontaneously Hypertensive Rats. Cancer Chemother. Pharmacol. 1994;35:93–100. doi: 10.1007/BF00686629. PubMed DOI

Herman E.H., Ferrans V., Young R.S.K., Hamlin R.L. Effects of Pretreatment with ICRF-187 on the Total Cumulative Dose of Doxorubicin Tolerated by Beagle Dogs. Cancer Res. 1988;48:6918–6925. PubMed

Herman E.H., El-Hage A., Ferrans V. Protective Effects of ICRF-187 on Doxorubicin-Induced Cardiac and Renal Toxicity in Spontaneously Hypertensive Rats. Toxicol. Appl. Pharmacol. 1988;92:42–53. doi: 10.1016/0041-008X(88)90226-8. PubMed DOI

Alderton P.M., Gross J., Green M.D. Comparative Study of Doxorubicin, Mitoxantrone, and Epirubicin in Combination with ICRF-187 (ADR-529) in Chronic Cardiotoxicity Animal Model. Cancer Res. 1992;52:194–201. PubMed

Green D., Bensley D., Schein P. Preclinical Evaluation of WR-151327: An Orally Active Chemotherapy Protector. Cancer Res. 1994;54:738–741. PubMed

Meriweather V.D., Bachur N.R. Inhibition of DNA and RNA Metabolism by Daunomycin and Adriamycin in L1210 Mouse Leukemia. Cancer Res. 1972;32:1137–1142. PubMed

Castaldi G., Zavagli G. Migration of the Macrophages to the Thymus after Cyclophosphamide. Br. J. Exp. Pathol. 1972;53:28–30. PubMed PMC

List A.F., Heaton R., Glinsmann-Gibson B., Capizzi R.L. Amifostine Stimulates Formation of Multipotent and Erythroid Bone Marrow Progenitors. Leukemia. 1998;12:1596–1602. doi: 10.1038/sj.leu.2401151. PubMed DOI

Douau L., Hu C., Giarratana M.C. Amifostine Improves the Antileukemic Therapeutic Index of Mafosfamide: Implications for Bone Marrow Purging. Blood. 1995;86:2849–2855. PubMed

Romano M.F., Lamberti A., Bisogni R., Garbi C., Pagnano A.M., Auletta P., Tassone P., Turco M.C., Venuta S. Amifostine Inhibits Hematopoietic Progenitor Cell Apoptosis by Activating NF-κB/Rel Transcription Factors. Blood. 1999;94:4060–4066. PubMed

List A.F., Heaton R., Glinsmann-Gibson B. Amifostine is a Potent Stimulant of Hematopoietic Progenitors. Proc. Am. Assoc. Cancer Res. 1995;36:291.

Ridgway D.D., Borzy S.M., Bagby C.M. Granulocyte Macrophage Colony-Stimulating Activity Production by Cultured Human Thymic Nonlymphoid Cells Is Regulated by Endogenous Interleukin 1. Blood. 1988;72:1230–1236. PubMed

Schwartz N.G., Patchen L.M., Neta R., MacVittie T.J. Radioprotection of Mice with Interleukin 1: Relationship to the Number of Spleen Colony-Forming Units. Radiat. Res. 1989;119:101–112. doi: 10.2307/3577370. PubMed DOI

Neta R., Szein B.M., Oppenheim J.J., Gillis S., Douches D.S. The In Vivo Effects of Interleukin 1. I. Bone Marrow Cells Are Induced to Cycle after Administration of Interleukin 1. J. Immunol. 1987;139:1861–1866. PubMed

Schmalbach T.K., Borch R.F. Mechanism of Diethyldithiocarbamate Modulation of Murine Bone Marrow Toxicity. Cancer Res. 1990;50:6218–6221. PubMed

Eppstein D.A., Kurahara C.G., Bruno A.B., Terrell G. Prevention of Doxorubicin-Induced Hematotoxicity in Mice by Interleukin 1. Cancer Res. 1989;49:3955–3960. PubMed

Bertani T., Poggi A., Pozzoni R., Delani F., Sacchi G., Thoua Y., Mecca G., Remuzzi G., Donati M.B. Adriamycin-Induced Nephrotic Syndrome in Rats. Sequence of Pathologic Events. Lab. Investig. 1982;46:16–23. PubMed

Okuda S., Oh Y., Tsuruda H., Onoyama K., Fujumi S., Fujishima M. Adriamycin-Induced Nephropathy as a Model of Chronic Progressive Glomerular Disease. Kidney Int. 1986;29:502–510. doi: 10.1038/ki.1986.28. PubMed DOI

Rašković A., Stilinović N., Kolarović J., Vasović V., Vukmirović S., Mikov M. The Protective Effects of Silymarin against Doxorubicin-Induced Cardiotoxicity and Hepatotoxicity in Rats. Molecules. 2011;16:8601–8613. doi: 10.3390/molecules16108601. PubMed DOI PMC

Su Z., Ye J., Qin Z., Ding X. Protective Effects of Madecassoside against Doxorubicin Induced Nephrotoxicity in Vivo and in Vitro. Sci. Rep. 2015;5:18314. doi: 10.1038/srep18314. PubMed DOI PMC

King P., Perry M. Hepatotoxicity of Chemotherapy. Oncologist. 2001;6:162–176. doi: 10.1634/theoncologist.6-2-162. PubMed DOI

Lee C.S., Tkacs N.C. Current Concepts of Neurohormonal Activation in Heart Failure: Mediators and Mechanisms. AACN Adv. Crit. Care. 2008;19:364–385. doi: 10.1097/01.AACN.0000340718.93742.c4. PubMed DOI

Rea M.E., Dunlap M.E. Renal Hemodynamics in Heart Failure: Implications for Treatment. Curr. Opin. Nephrol. Hypertens. 2008;17:87–92. doi: 10.1097/MNH.0b013e3282f357da. PubMed DOI

Boulanger C.M. Secondary Endothelial Dysfunction: Hypertension and Heart Failure. J. Mol. Cell. Cardiol. 1999;31:39–49. doi: 10.1006/jmcc.1998.0842. PubMed DOI

Chaggar P.S., Malkin C.J., Shaw S.M., Williams S.G., Channer K.S. Neuroendocrine Effects on the Heart and Targets for Therapeutic Manipulation in Heart Failure. Cardiovasc. Ther. 2009;27:187–193. doi: 10.1111/j.1755-5922.2009.00094.x. PubMed DOI

El-Sayed M., Mansour A.M., El-Sawy W.S. Protective Effect of Proanthocyanidins against Doxorubicin-Induced Nephrotoxicity in Rats. J. Biochem. Mol. Toxicol. 2017;31 doi: 10.1002/jbt.21965. PubMed DOI

Petrovic D., Seke M., Labudovic-Borovic M., Jovic D., Borisev I., Srdjenovic B., Rakocevic Z., Pavlovic V., Djordjevic A. Hepatoprotective Effect of Fullerenol/Doxorubicin Nanocomposite in Acute Treatment of Healthy Rats. Exp. Mol. Pathol. 2018;104:199–211. doi: 10.1016/j.yexmp.2018.04.005. PubMed DOI

Marzatico F., Porta C., Moroni M., Bertorelli L., Borasio E., Finotti N., Pansarasa O., Castagna L. In Vitro Antioxidant Properties of Amifostine (WR-2721, Ethyol) Cancer Chemother. Pharmacol. 2000;45:172–176. doi: 10.1007/s002800050026. PubMed DOI

Bjelogrlic S.K., Lukic S.T., Djuricic S.M. Activity of Dexrazoxane and Amifostine against Late Cardiotoxicity Induced by the Combination of Doxorubicin and Cyclophosphamide In Vivo. Basic Clin. Pharmacol. Toxicol. 2013;113:228–238. doi: 10.1111/bcpt.12086. PubMed DOI

Shokrzadeh M., Ghassemi-Barghi N. Antioxidant and Genoprotective Effects of Amifostine against Irinotecan Toxicity in Human Hepatoma Cells. Int. J. Cancer Res. Ther. 2018;3:1–5.

Jacevic V., Kuca K., Milovanovic Z., Bocarov-Stancic A., Rancic I., Bokonjic D., Dragojevic-Simic V., Segrt Z. Gastroprotective Effects of Amifostine in Rats Treated by T-2 Toxin. Toxicol. Rev. 2018;37:123–127. doi: 10.1080/15569543.2017.1329211. DOI

Jensen R.A. Doxorubicin Cardiotoxicity: Contractile Changes after Long Term Treatment in the Rat. J. Pharmacol. Exp. Ther. 1986;236:197–203. PubMed

Jacevic V., Jovic D., Kuca K., Dragojevic-Simic V., Dobric S., Trajkovic S., Borisev I., Segrt Z., Milovanovic Z., Bokonjic D., et al. Effects of Fullerenol Nanoparticles and Amifostine on Radiation-Induced Tissue Damages: Histopathological Analysis. J. Appl. Biomed. 2016;14:285–297. doi: 10.1016/j.jab.2016.05.004. DOI

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Protective Effects of Simvastatin on Endotoxin-Induced Acute Kidney Injury through Activation of Tubular Epithelial Cells' Survival and Hindering Cytochrome C-Mediated Apoptosis

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