Prevention of radiation-induced liver and kiney toxicity: a role for amifostine

Abstract

OBJECTIVES To investigate the protective effect of amifostine against radiation induced liver and kidney injury of rats, using scintigraphic and histopathologic parameters. METHODS Female Wistar Albino rats were randomly allocated to 3 groups: control, radiotherapy alone (RT), and amifostine+RT (n=10). Single-dose of 600 cGy X-ray was performed with a single field compromised liver and right kidney. Amifostine was administered intraperitoneally at a dose of 400 mg/kg, 30 minutes before irradiation. Scintigraphic evaluation was performed before irradiation and the end of the study at 6 nd month. Histopathologic examinations were performed post mortem. RESULTS A clear protective effect of amifostine against radiation-induced late damage in liver and kidney was found with scintigraphic evaluation. In addition, amifostine reduced the decrease of histopathologic changes for both of the tissues. CONCLUSION The results showed that amifostine significantly reduced radiation-induced liver and kidney toxicity and therefore warrant additional study in a clinically relevant fractionated model.

Keywords

• Amifostine,Radiation Effects,Radiotherapy,Adverse effects,Toxicity,Radionuclide Imaging,Histopathology,Rats, Wistar,Models, Animal,Liver,Kidney,Radiation Oncology

Radyasyona bağlı oluşan karaciğer ve böbrek toksitesini önlemede amifostinin rolü

Öz

AMAÇ Amifostinin karaciğer ve böbrek dokusu üzerine olan radyoprotektif etkisini sintigrafik ve histopatolojik yöntemlerle değerlendirmek. GEREÇ VE YÖNTEM Dişi Wistar Albino cinsi sıçanlar 3 gruba randomize edildi: kontrol grubu, sadece radyoterapi (RT) grubu ve amifostine+RT grubu (n=10, her grup). Karaciğer ve böbreği kapsayan tek alandan 600 cGy RT uygulandı. Amifostine ise RT'de 30 dakida önce 400 mg/kg intraperitoneal olarak verildi. Sıçanlar 6 ay takip edildi. Sintigrafik değerlendirme RT öncesi ve deneyi sonlandırmadan önce yapıldı. Postmortem dönemde ise dokular histopatolojik olarak değerlendirildi. BULGULAR Amifostinin karaciğer ve böbrek üzerine radyoprotektif etkisi sintigrafik olarak kanıtlanmıştır. Bununla birlikte, radyasyona bağlı histopatolojik değişiklikleri her iki dokuda da azaltmıştır. SONUÇ Sonuçlarımızın klinik çalışmalarla değerlendirilmesi uygun olacaktır.

Anahtar Kelimeler

• Amifostin, böbrek/radyasyon etkisi, karaciğer/radyasyon etkisi, radyoterapi/yan etki, risk faktörleri, toksisite

References

1. 1. Curran WJ. Radiation-induced toxicities: the role of radioprotectants. Semin Radiat Oncol. 1998;8(4 Suppl 1):2-4.
2. 2. Beauvois S, Van Houtte P. Late effects of radiations on the kidney. [Article in French] Cancer Radiother 1997;1(6):760-3. [Abstract]
3. 3. Geraci JP, Mariano MS, Jackson KL. Hepatic radiation injury in the rat. Radiat Res 1991;125(1):65-72.
4. 4. Williams MV, Denekamp J. Modification of the radiation response of the mouse kidney by misonidazole and WR-2721. Int J Radiat Oncol Biol Phys 1983;9(11):1731-6.
5. 5. Ramadan LA, Shouman SA, Sayed-Ahmed MM, ElHabit OH. Modulation of radiation-induced organs toxicity by cremophor-el in experimental animals. Pharmacol Res 2001;43(2):185-91.
6. 6. Ramadan LA, Roushdy HM, Abu Senna GM, Amin NE, El-Deshw OA. Radioprotective effect of silymarin against radiation induced hepatotoxicity. Pharmacol Res 2002;45(6):447-54.
7. 7. Donaldson SS, Moskowitz PS, Evans JW, Fajardo LF. Protection from radiation nephropathy by WR-2721. Radiat Res 1984;97(2):414-23.
8. 8. Jirtle RL, Pierce LJ, Crocker IR, Strom SC. Radiation protection of rat parenchymal hepatocytes with S-2- (3-aminopropylamino)ethylphosphorothioic acid. Radiother Oncol 1985;4(3):231-7.

9. 9. Hwang JM, Chan DC, Chang TM, Tsao TY, Tsou SS, Lu RH, et al. Effects of oral arginine and glutamine on radiation-induced injury in the rat. J Surg Res 2003;109(2):149-54.
10. 10.Inomata T, Itoh S, Kariya S, Mesaki K, Nishioka A, Ogawa Y, et al. Late pathologic changes in guinea pig kidneys irradiated with conventional fractionation and hyperfractionation. Int J Radiat Oncol Biol Phys 1999;44(1):171-7.
11. 11. Wrembel-Wargocka J, Jabslonska H, Chomiczewski K. Clinical use of Amifostine (WR-2721) as a preparation protecting healthy tissues from the cytotoxic effects of chemotherapy and radiation therapy. Przegl Lek 1996;53(11):820-5.
12. 12. Schuchter LM, Hensley ML, Meropol NJ, Winer EP; American Society of Clinical Oncology Chemotherapy and Radiotherapy Expert Panel. 2002 update of recommendations for the use of chemotherapy and radiotherapy protectants: clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol 2002;20(12):2895-903.
13. 13.Rasey JS, Nelson NJ, Mahler P, Anderson K, Krohn KA, Menard T. Radioprotection of normal tissues against gamma rays and cyclotron neutrons with WR- 2721: LD50 studies and 35S-WR-2721 biodistribution. Radiat Res 1984;97(3):598-607.
14. 14.Cassady JR. Clinical radiation nephropathy. Int J Radiat Oncol Biol Phys 1995;31(5):1249-56.
15. 15. Schuchter LM. Guidelines for the administration of amifostine. Seminars in Oncology 1996; Vol 23, No 4, Suppl 8:40-3.
16. 16. Dewit L, Anninga JK, Hoefnagel CA, Nooijen WJ. Radiation injury in the human kidney: a prospective analysis using specific scintigraphic and biochemical endpoints. Int J Radiat Oncol Biol Phys 1990;19(4):977-83.
17. 17. Spencer CM, Goa KL. Amifostine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential as a radioprotector and cytotoxic chemoprotector. Drugs 1995;50(6):1001-31.
18. 18.Capizzi RL. Clinical status and optimal use of amifostine. Oncology (Williston Park) 1999;13(1):47-59.
19. 19. Kemp G, Rose P, Lurain J, Berman M, Manetta A, Roullet B, et al. Amifostine pretreatment for protection against cyclophosphamide-induced and cisplatininduced toxicities: results of a randomized control trial in patients with advanced ovarian cancer. J Clin Oncol 1996;14(7):2101-12.
20. 20. Symon Z, Levi M, Ensminger WD, Smith DE, Lawrence TS. Selective radioprotection of hepatocytes by systemic and portal vein infusions of amifostine in a rat liver tumor model. Int J Radiat Oncol Biol Phys 2001;50(2):473-8.