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Ratlarda Radyoterapiye Bağlı Renal Toksisitede Mesnanın Koruyucu Rolü

Year 2020, Volume: 6 Issue: 1, 66 - 72, 01.01.2020

Abstract

Amaç: Sodyum 2-merkaptoethanosülfonat mesna alkilleyici antineoplastik ilaçlardan siklofosfamid ve ifosfomidin neden olduğu hemorajik sistiti ve nefrotoksisiteyi önlediği bilinen sentetik bir tiyoldür. Mesnanın küçük moleküler yapısı, böbrekte konsantre olma özelliği, tübüler epitelde aktif –SH bileşiklerine dönüşmesi ve antioksidan potansiyeli ile böbreklerdeki radyasyon hasarını engellemekte faydalı olabileceğini düşündük.Gereç ve Yöntemler: Bu deneysel çalışma 8 haftalık 24 Sprague-Dawley ratları ile yapılmıştır. Her grupta 6 rat olmak üzere 4 grup oluşturuldu. Grup I: Sadece serum fizyolojik uygulandı. Grup II: Sadece mesna uygulandı. Grup III: Mesna, 5 gün boyunca radyoterapiden 20 dakika önce verildi. Grup IV: İki paralel alandan 6 MV foton ile, 400 cGy'lik fraksiyonlarla toplam 20 Gy doz bilateral böbreklere uygulandı

References

  • 1. Luxton RW, Kunkler PB. Radiation nephritis. Acta Radiologica: Therapy, Physics, Biology. 1964; 2:169-78.
  • 2. Jongejan HT, van der Kogel AJ, Provoost AP, Molenaar JC. Radiation nephropathy in young and adult rats. International Journal of Radiation Oncology, Biology, Physics 1987; 13(2):225-32.
  • 3. Nair CK, Parida DK, Nomura T. Radioprotectors in radiotherapy. Journal of Radiation Research. 2001; 42(1):21-37.
  • 4. Zaki EL, Springate JE, Taub M. Comparative toxicity of ifosfamide metabolites and protective effect of mesna and amifostine in cultured renal tubule cells. Toxicology in Vitro 2003; 17(4):397-402.
  • 5. James CA, Mant TG, Rogers HJ. Pharmacokinetics of intravenous and oral sodium 2-mercaptoethane sulphonate (mesna) in normal subjects. British Journal of Clinical Pharmacology 1987; 23(5):561-8.
  • 6. Ormstad K, Uehara N. Renal transport and disposition of Na-2-mercaptoethane sulfonate disulfide (dimesna) in the rat. FEBS Letters 1982; 150(2):354-8.
  • 7. Mashiach E, Sela S, Weinstein T, Cohen HI, Shasha SM, Kristal B. Mesna: A novel renoprotective antioxidant in ischaemic acute renal failure. Nephrology, Dialysis, Transplantation 2001; 16(3):542-51.
  • 8. Skinner R, Sharkey IM, Pearson AD, Craft AW. Ifosfamide, mesna, and nephrotoxicity in children. Journal of Clinical Oncology 1993; 11(1):173-90.
  • 9. Mohrmann M, Ansorge S, Schonfeld B, Brandis M. Dithio-bis-mercaptoethanesulphonate (DIMESNA) does not prevent cellular damage by metabolites of ifosfamide and cyclophosphamide in LLC-PK1 cells. Pediatric Nephrology (Berlin, Germany) 1994; 8(4):458-65.
  • 10. Zheng S, Newton GL, Gonick G, Fahey RC, Ward JF. Radioprotection of DNA by thiols: relationship between the net charge on a thiol and its ability to protect DNA. Radiation Research 1988;114(1):11-27.
  • 11. Hensley ML, Schuchter LM, Lindley C, Meropol NJ, Cohen GI, Broder G, Gradishar WJ, Green DM, Langdon RJ Jr, Mitchell RB, Negrin R, Szatrowski TP, Thigpen JT, Von Hoff D, Wasserman TH, Winer EP, Pfister DG. American Society of Clinical Oncology clinical practice guidelines for the use of chemotherapy and radiotherapy protectants. Journal of Clinical Oncology 1999; 17(10):3333-55.
  • 12. Brade WP, Herdrich K, Varini M. Ifosfamide-- pharmacology, safety and therapeutic potential. Cancer Treatment Reviews 1985; 12(1):1-47.
  • 13. Lima MV, Ferreira FV, Macedo FY, de Castro Brito GA, Ribeiro RA. Histological changes in bladders of patients submitted to ifosfamide chemotherapy even with mesna prophylaxis. Cancer Chemotherapy and Pharmacology 2007; 59(5):643-50.
  • 14. Yildirim I, Korkmaz A, Oter S, Ozcan A, Oztas E. Contribution of antioxidants to preventive effect of mesna in cyclophosphamide-induced hemorrhagic cystitis in rats. Cancer Chemotherapy and Pharmacology 2004; 54(5):469-73.
  • 15. Lord-Fontaine S, Averill DA. Enhancement of cytotoxicity of hydrogen peroxide by hyperthermia in chinese hamster ovary cells: role of antioxidant defenses. Archives of Biochemistry and Biophysics 1999; 363(2):283-95.
  • 16. Kabasakal L, Sehirli AO, Cetinel S, Cikler E, Gedik N, Sener G. Mesna (2-mercaptoethane sulfonate) prevents ischemia/reperfusion induced renal oxidative damage in rats. Life Sciences 2004; 75(19):2329-40.
  • 17. Ormstad K, Orrenius S, Lastbom T, et al. Pharmacokinetics and metabolism of sodium 2-mercaptoethanesulfonate in the rat. Cancer Research 1983; 43(1):333-8.
  • 18. Moulder JE, Fish BL. Age dependence of radiation nephropathy in the rat. Radiation Research 1997; 147(3):349-53.
  • 19. Cohen EP, Molteni A, Hill P, Fish BL, Ward WF, Moulder JE, Carone FA. Captopril preserves function and ultrastructure in experimental radiation nephropathy. Laboratory Investigation 1996; 75(3):349-60.
  • 20. Hensley ML, Hagerty KL, Kewalramani T, Green DM, Meropol NJ, Wasserman TH, Cohen GI, Emami B, Gradishar WJ, Mitchell RB, Thigpen JT, Trotti A 3rd, von Hoff D, Schuchter LM. American Society of Clinical Oncology 2008 clinical practice guideline update: Use of chemotherapy and radiation therapy protectants. Journal of Clinical Oncology 2009; 27(1):127-45.
  • 21. Morais MM, Belarmino-Filho JN, Brito GA, Ribeiro RA. Pharmacological and histopathological study of cyclophosphamide-induced hemorrhagic cystitis - comparison of the effects of dexamethasone and Mesna. Brazilian Journal of Medical and Biological Research 1999; 32(10):1211-5.
  • 22. Themann H, Oberdorf E, Brock N, Pohl J. Electron microscopic investigations of the cyclophosphamideinduced lesions of the urinary bladder of the rat and their prevention by mesna. Urologia Internationalis 1987; 42(1):37-43.

The Protective Role of Mesna in Renal Toxicity Associated with Radiotherapy in Rats

Year 2020, Volume: 6 Issue: 1, 66 - 72, 01.01.2020

Abstract

Objective: Sodium 2-mercaptoethanosulphinate mesna is a synthetic thiol known to prevent hemorrhagic cystitis and nephrotoxicity induced by alkylating anti- neoplastic drugs such as cyclophosphamide and iphosphamide. We proposed that mesna might be effective on protection of radiation induced renal injuries because of its low molecular weight, its ability to concentrate in the kidneys, its conversion to active -SH compounds in the tubular epithelium and its antioxidant potential.Material and Methods: This experimental study was carried out on 24 8-week old SpragueDawley rats. The rats were allocated into 4 groups, 6 rats in each. Group I: Only saline solution was infused. Group II: Only mesna was infused. Group III: Mesna was infused, 20 minutes before radiotherapy, for 5 days. Group IV: Radiotherapy was given bilaterally to the kidneys at a dose of 20 Gy, in 400cGy fractions, using 6 MV photon in two parallel fields.Results: There was no statistical difference between the radiotherapy and radiotherapy+mesna groups in terms of creatinine clearance p>0.05 . However; there was statistically significant difference between the control group and radiotherapy/mesna+radiotherapy in terms of blood BUN levels p0.05 .Conclusion: Our study may pioneer studies searching for other agents instead of mesna for preventing hemorrhagic cystitis induced by cyclophosphamide and iphosphamide because it showed that mesna cannot protect kidneys from radiation nephrotoxicity on histopathologic evaluation. This is also the first study demonstrating ineffectiveness of mesna as a radioprotectant

References

  • 1. Luxton RW, Kunkler PB. Radiation nephritis. Acta Radiologica: Therapy, Physics, Biology. 1964; 2:169-78.
  • 2. Jongejan HT, van der Kogel AJ, Provoost AP, Molenaar JC. Radiation nephropathy in young and adult rats. International Journal of Radiation Oncology, Biology, Physics 1987; 13(2):225-32.
  • 3. Nair CK, Parida DK, Nomura T. Radioprotectors in radiotherapy. Journal of Radiation Research. 2001; 42(1):21-37.
  • 4. Zaki EL, Springate JE, Taub M. Comparative toxicity of ifosfamide metabolites and protective effect of mesna and amifostine in cultured renal tubule cells. Toxicology in Vitro 2003; 17(4):397-402.
  • 5. James CA, Mant TG, Rogers HJ. Pharmacokinetics of intravenous and oral sodium 2-mercaptoethane sulphonate (mesna) in normal subjects. British Journal of Clinical Pharmacology 1987; 23(5):561-8.
  • 6. Ormstad K, Uehara N. Renal transport and disposition of Na-2-mercaptoethane sulfonate disulfide (dimesna) in the rat. FEBS Letters 1982; 150(2):354-8.
  • 7. Mashiach E, Sela S, Weinstein T, Cohen HI, Shasha SM, Kristal B. Mesna: A novel renoprotective antioxidant in ischaemic acute renal failure. Nephrology, Dialysis, Transplantation 2001; 16(3):542-51.
  • 8. Skinner R, Sharkey IM, Pearson AD, Craft AW. Ifosfamide, mesna, and nephrotoxicity in children. Journal of Clinical Oncology 1993; 11(1):173-90.
  • 9. Mohrmann M, Ansorge S, Schonfeld B, Brandis M. Dithio-bis-mercaptoethanesulphonate (DIMESNA) does not prevent cellular damage by metabolites of ifosfamide and cyclophosphamide in LLC-PK1 cells. Pediatric Nephrology (Berlin, Germany) 1994; 8(4):458-65.
  • 10. Zheng S, Newton GL, Gonick G, Fahey RC, Ward JF. Radioprotection of DNA by thiols: relationship between the net charge on a thiol and its ability to protect DNA. Radiation Research 1988;114(1):11-27.
  • 11. Hensley ML, Schuchter LM, Lindley C, Meropol NJ, Cohen GI, Broder G, Gradishar WJ, Green DM, Langdon RJ Jr, Mitchell RB, Negrin R, Szatrowski TP, Thigpen JT, Von Hoff D, Wasserman TH, Winer EP, Pfister DG. American Society of Clinical Oncology clinical practice guidelines for the use of chemotherapy and radiotherapy protectants. Journal of Clinical Oncology 1999; 17(10):3333-55.
  • 12. Brade WP, Herdrich K, Varini M. Ifosfamide-- pharmacology, safety and therapeutic potential. Cancer Treatment Reviews 1985; 12(1):1-47.
  • 13. Lima MV, Ferreira FV, Macedo FY, de Castro Brito GA, Ribeiro RA. Histological changes in bladders of patients submitted to ifosfamide chemotherapy even with mesna prophylaxis. Cancer Chemotherapy and Pharmacology 2007; 59(5):643-50.
  • 14. Yildirim I, Korkmaz A, Oter S, Ozcan A, Oztas E. Contribution of antioxidants to preventive effect of mesna in cyclophosphamide-induced hemorrhagic cystitis in rats. Cancer Chemotherapy and Pharmacology 2004; 54(5):469-73.
  • 15. Lord-Fontaine S, Averill DA. Enhancement of cytotoxicity of hydrogen peroxide by hyperthermia in chinese hamster ovary cells: role of antioxidant defenses. Archives of Biochemistry and Biophysics 1999; 363(2):283-95.
  • 16. Kabasakal L, Sehirli AO, Cetinel S, Cikler E, Gedik N, Sener G. Mesna (2-mercaptoethane sulfonate) prevents ischemia/reperfusion induced renal oxidative damage in rats. Life Sciences 2004; 75(19):2329-40.
  • 17. Ormstad K, Orrenius S, Lastbom T, et al. Pharmacokinetics and metabolism of sodium 2-mercaptoethanesulfonate in the rat. Cancer Research 1983; 43(1):333-8.
  • 18. Moulder JE, Fish BL. Age dependence of radiation nephropathy in the rat. Radiation Research 1997; 147(3):349-53.
  • 19. Cohen EP, Molteni A, Hill P, Fish BL, Ward WF, Moulder JE, Carone FA. Captopril preserves function and ultrastructure in experimental radiation nephropathy. Laboratory Investigation 1996; 75(3):349-60.
  • 20. Hensley ML, Hagerty KL, Kewalramani T, Green DM, Meropol NJ, Wasserman TH, Cohen GI, Emami B, Gradishar WJ, Mitchell RB, Thigpen JT, Trotti A 3rd, von Hoff D, Schuchter LM. American Society of Clinical Oncology 2008 clinical practice guideline update: Use of chemotherapy and radiation therapy protectants. Journal of Clinical Oncology 2009; 27(1):127-45.
  • 21. Morais MM, Belarmino-Filho JN, Brito GA, Ribeiro RA. Pharmacological and histopathological study of cyclophosphamide-induced hemorrhagic cystitis - comparison of the effects of dexamethasone and Mesna. Brazilian Journal of Medical and Biological Research 1999; 32(10):1211-5.
  • 22. Themann H, Oberdorf E, Brock N, Pohl J. Electron microscopic investigations of the cyclophosphamideinduced lesions of the urinary bladder of the rat and their prevention by mesna. Urologia Internationalis 1987; 42(1):37-43.
There are 22 citations in total.

Details

Primary Language English
Journal Section Research Article
Authors

Eda Küçüktülü This is me

Ahmet Fatih Yürekli This is me

Murat Topbaş This is me

Engin Yenilmez This is me

Uzer Küçüktülü This is me

Publication Date January 1, 2020
Published in Issue Year 2020 Volume: 6 Issue: 1

Cite

APA Küçüktülü, E., Yürekli, A. F., Topbaş, M., Yenilmez, E., et al. (2020). The Protective Role of Mesna in Renal Toxicity Associated with Radiotherapy in Rats. Akdeniz Tıp Dergisi, 6(1), 66-72.