THE EFFECTS OF VERAPAMIL, A CALCIUM CANAL BLOKER, ON CISPLATIN TOXICITY

Abstract

The aim of this study was investigated to protective effects of calcium chanel blocker verapamil on cisplatin induced toxicity.Fourty-two Rattus norvegicus (Wistar albino) rats were divided into six groups. The control group (I. group) was injected with 0.3 ml saline, II. group was injected with 0.2 mg/kg verapamil, III. group was injected with  2 mg/kg verapamil, IV. group was injected with 5 mg/kg cisplatin, V. group was injected with 0.2 mg/kg verapamil+5 mg/kg cisplatin and VI. group was injected with 2 mg/kg verapamil+5 mg/kg cisplatin. Before cisplatin injection, verapamil was given during the three days at the same hour. After this period, at the fourth day, cisplatin was injected with as a single dose. Following the last dose, within 24 hours urine samples were collected and than blood, kidney and liver tissues samples and bone marrow were collected from the rats under ether anesthesia.At the end of the study, we found that serum creatinine in the IV. group was significantly increased according to control group (p<0.001). SGOT activity was significantly decreased in III., V. and VI. groups (p<0.001). As a result of chromosomal analyses,  there were not significantly increased on the number of chromatid typed gaps in the IV., V ve VI. group according to control group. Histopathologic findings showed that a certain recovery was dedected into  kidney tissue of the V. group according to kidney tissue of  IV.group .As a conclusion, it was determined that verapamil had a protective effect on cisplatin toxicity and this protective effect was  high  in the V. group which had been given low dose of verapamil. 

Keywords

• Cisplatin,Rat,Toxicity,Verapamil

CİSPLATİN TOKSİSİTESİ ÜZERİNE KALSİYUM KANAL BLOKÖRLERİNDEN VERAPAMİL'İN ETKİLERİ

Abstract

Bu çalışmanın amacı, antineoplastik bir ajan olan cisplatinin toksisitesi üzerine, kalsiyum kanal blokörü olan verapamilin etkilerini araştırmaktır.Bu çalışmada, 42 adet Rattus norvegicus (Wistar albino) soyu, 180-270 g ağırlığında sıçan kullanıldı. Sıçanlar eşit sayıda 6 gruba ayrıldı. Kontrol grubu olan I. gruba 0,3 ml serum fizyolojik, II. gruba 0,2 mg/kg verapamil, III. gruba 2 mg/kg verapamil, IV. gruba 5 mg/kg cisplatin, V. gruba 0,2 mg/kg verapamil ile 5 mg/kg cisplatin ve VI. gruba da 2 mg/kg verapamil ile 5 mg/kg cisplatin verildi. Deneyde, verapamil, cisplatin enjeksiyonundan önce 3 gün boyunca her gün aynı saatte, cisplatin ise verapamil enjeksiyonunun bitiminden sonraki 4. günde tek doz halinde, intraperitoneal olarak uygulandı. Cisplatin enjeksiyonunu takiben 24 saatlik idrar örnekleri toplandı ve deney bitiminde eter anestezisi altında kan, doku ve kemik iliği örnekleri alındı.Çalışma sonunda, kontrole göre sadece cisplatin verilen IV. grupta, serum kreatinin değerinde istatistiksel olarak anlamlı derecede artış bulundu (p<0.001). III., V. ve VI. grupta ise, SGOT aktivitesi (p<0.01) önemli düzeyde azaldı. Kromozomal incelemede de IV., V. ve VI. gruplarda kromatid tipi gap sayısında artış görülse de bu artış kontrole göre anlamlı değildi. Histopatolojik bulgular düşük doz verapamil verdiğimiz V. grupta IV. gruba göre, böbrek dokusunda  belirgin bir iyileşme olduğunu gösterdi.Sonuç olarak bu çalışmada, cisplatinin toksisitesi üzerine bazı bulgularda verapamilin koruyucu etki yaptığı, bu koruyucu etkinin düşük doz verapamil verilen V. grupta daha da etkili olduğu tespit edildi.

Keywords

• Cisplatin,Sıçan,Toksisite,Verapamil

References

1. [1] S.O. Kayaalp, Rasyonel Tedavi Yönünden Tıbbi Farmokoloji. 9. Baskı, I. Cilt. Hacettepe-Taş Kitapçılık Ltd. Şti., Ankara (2000), 372 – 400.
2. [2] T. Godfraind, R. Miller, M Wibo M, Calcium Antogonism And Calcium Entry Blockade. Pharmacol Rev, 38:(4), (1986) 321– 416,.
3. [3] A.L. Haris, D. Hochhause, Mechanisms of Multidrug Resistance in Cancer Treatmen, Acta Oncologica, 31:(2), (1992), 205 – 213.
4. [4] J.D.Bitran , R.K.Desser, A.A Billings, M.F. Kozloff, et a,. Acute Nephrotoxicity Following cis–dichlorodinammine–platinium, Cancer, 49 (1982), 1784–1788.
5. [5] J.D. Blachiey, J.B. Mill, Renal and Electrolyte Disturbances Associated with Cisplatin, Annals of Internal Medicine, 95 (1981): 628– 632.
6. [6] K. Hanada , K. Odaka, A. Kuda , H. Ogata, Effects of Disopyramide and Verapamil on Renal Disposition and Nephrotoxicity of Cisplatin in Rats. Pharmaceutical Research, 16:(10), (1999) : 1589-1595.
7. [7] Y. Miyamato, K. Shimado, Y. Sakaguchi, M. Miyamato, Cisplatin (CDDP)_İnduced Acute Toxicity in an Experimental Model of Hepatic Fibrosis. The Journal of Toxicological Sciences, 32:(39), (2007), 311-319.
8. [8] H.S. So, C. Park , H.J Kim., J.H. Lee et al, Protective Effect of T-Type Calcium Channel Blocker Flunarizine on Cisplatin- Induced Death of Auditory Cells Hearing Research, 204 (2005), 127-13,

9. [9] E. Kurt., T. Evrensel, G. Gönüllü, Ö. Kanat ve ark, Cisplatine Bağlı Böbrek Toksisitesi ve Sentetik Oral Prostaglandin E. Uludağ Üniversitesi Tıp Fakültesi Dergisi, 28 (2), (2002), 17-20.
10. [10] AK Campell. What does Ca+2 do in cells?, Cell Calsium, 7 (1986), 285– 286,.
11. [11] K. Umeshita, M. Manden., T. Ukei et al, Different Cytoprotective Effects of Calcium Blockers in Hypotermic Liver Preservation, Transplantation Proceedings, 21(1), (1989),1290–1291.
12. [12] NA.Yıldızoğlu, VM Altan, Y Öztürk, Kalsiyum Kanalları ve Kalsiyum Antogonistleri, Doğa, 13(3), (1989), 274 – 284.
13. [13] K.A. Duggan, G.. Macdonald., J.A. Charlesworth., B.A. Pussell, Verapamil Prevents Post–Transplant Oliguric Renal Failure, Clinical Nephrology, 24(6), (1985), 289 – 291.
14. [14] F. Murad, Calcium Channel Blockers, Goodman and Gilmon's The Pharmocological Basis of Therapetics, Edited by Gilman AG., Rall TW., Nies AS. and Taylor P., 8th ed., Progamen Press, New York (1990), 774 – 783 pp.
15. [15] P.L Vaghy., J.S. Williams., A. Schwart, Reseptor Pharmacology Of Cacium Entry Blocing Agents, Am J Cardiol, 59 (1987), 9 –17A.
16. [16] R.W. Schrier., P.E. Arnold., W.J.V. Putten., T.J. Burke, Celluler Calcium in Ischemic Acute Renal Failure:Role of Calcium Entry Blokers, Kidney International, 32 (1987), 313–312.
17. [17] M. Liao., H. Chen., H Shui, Apoptosis Induced by Cisplatin and Verapamil or SDZ PSC 833 in Human Ovarian Cell Lines. Zhonghua Fu Chan Ke Za Zhi, 35(2), (2000), 101- 104.
18. [18] S. Kondo., T. Yin D.Morimura, J. Takeuchi, Combination Therapy with Cisplatin and Nifedipine Inducing Apoptosis in Multidrug Resistant Human Glioblastoma Cells. Br J Cancer, 71(2), (1995), 282- 289.
19. [19] M. Yenson, Tıpsal Ve Klinik Labaratuvar Çalışamaları. Geliştirilmiş 6. baskı. Sermet Matbaası, Beta Basım Yayım Dağıtım A.Ş., İstanbul, (1986).
20. [20] N. Başaran, Sitogenetik Laboratuvar El Kitabı. Eskişehir Anadolu Üniversitesi Tıp Fakültesi, Eskişehir, (1987), 38-40.
21. [21] J.D. Bancraft, A Stevens, Theory and Practice of Histological techniques, Churcill Livingstone, Edinburg, (1977), 240 – 245.
22. [22] T.J. Burke., P.E. Arnold., J.A. Gordon., et al, Protective Effect of İntrarenal Calcium Membrane Blockers Before of After Renal Ischemia, J Clin Invest, 74, (1984),1830-1840.
23. [23] G. Deray, M. Dubals, H. Beufils, et al, Efffects Of Nifedipine on Cisplatinum–Induced Nephrotoxicity In Rats, Clinical Nephrology, 30(3), (1988), 146–150.
24. [24] J. Levi, C. Jacobs, S.M. Kalman, et al, Mechaninism of Cis–Platinum Nephrotoksisity, Effects Of Sulfhydryl Groups In Rat Kidneys. The Joural of Pharmacology and Experimental Therapeutics, 213(3), (1980) 545–551.
25. [25] J.C. Gonzales–Vitale, D:M. Hayes, E, Cuitkovic, S.S Sternberg, The Renal Pathology In Clinical Trials of Cis–Platinum (II) Diammine–Dichloride, Cancer, 39, (1977), 1362–1371.
26. [26] D:M. Hayes, E. Cvitcovic, R.B. Golbey, et al, High Dose Cis–Platinum Diammine Dichloride: Amelioration of Renal Toxicity By Mannitol Diuresis, Cancer, 39, (1977), 1372–1381.
27. [27] R.F. Ozols, B.J. Corden, J. Jacob, High–Dose Cisplatin In Hypertonic Saline. Annals of Internal Medicine, 100(1), (1984),19–24.
28. [28] J.J. Stark, S.B. Howell, Nefrotoxicity of Cis–Platinum (II) Dichlorodiammine. Clin Pharmacol Ther, 23(4), (1978), 461–466.
29. [29] A.J. Watson, L.F. Gimenez, D.K. Klassen, et al, Calcium Channel Blockade In Experimental Aminoglycoside Nephrotocity, J Clin Pharmacol, 27, (1987), 625–627.
30. [30] N.P. Mora J.A. Cienfuegus, F. Pereira, et al, Value of Prostacyclin Plus Verapamil for Obtaining 24–Hour Preserved Liver Allografts, Transplantation Proceedings, 20(5), (1988), 980–982.
31. [31] K.Y. Polat, K. Karakaş, M. Başoğlu, et al, Protective Role of Verapamil and a–Tocopherol In Experimental Warm Liver Ischemia and Reperfusion Injury, Tr J of. Med Sci, 24, (1994), 29–43.
32. [32] Z.Z. Zdraveski, J.A. Melio, M.G. Marinus, J.M. Essigman, Multiple Phatways of Recombination define Cellular Responses to Cisplatin. Chemistry and Biology, 7, (2000), 39-50.
33. [33] A. Nowosielska, M.G. Marinus, Cisplatin Induces DNA Double-strand break Formation in Esharichia coli dam Mutations. DNA Repair 4, (2005), 773 -781.
34. [34] A. Nowosielska, M.G. Marinus, DNA Mismatch Repair-induced Double-strand Breaks. DNA Repair (2007) (Article in press).
35. [35] M.R. Brady, M.L. Zeidel, B.C. Kone, et al, Differential Actions of Cisplatin On Renal Proximal Tubule and Inner Medullary Collecting Duct Cells, The J Pharmacology and Experimental Theropeutics, 265(3), (1993), 1421–1428.
36. [36] G. Deray, M. Dubois, F. Martinee, et al, Protective Effects of Calcium Channel Blokers On Drug–Induced Nephrotoxicity, Therapie, 44, (1989), 183–187.
37. [37] B.R. Jones, R.B. Bhalla, J. Mladek, et al, Comparison of Methods of Evaluating Nephrotoxicity of Cis–Platinum, Clin Pharmacol Ther, 27(4), (1980), 557–562.
38. [38] J.J.G. Offerman, S. Meijer, D.T.H. Sleijfer, et al, The Influence Of Verapamil On Renal Function In Patients Treated With Ciplatin, Clinical Nephrology, 24(5), (1985), 249 – 255.
39. [39] R. Safirstein, P. Miller, J.B. Guttenplan, et al, Uptake and Metabolism of Cisplatin By Rat Kidney, Kidney International, 25, (1984),753–758.
40. [40] A. Başaran, Z. Eren, H.V. Güneş, et al, Effects of Verapamil On Gentamicin–İnduced Nephrotoxicity In Rats, J Healt Sci, 5, (1993),11– 21.
41. [41] C.D. Malis, J.Y. Cheung , A. Leaf. J.V. Bonventre, Effects of Verpamil In Models Of Ischemic Acute Renal Failure In The Rat, Clin Res, (1983), F735–F742,.
42. [42] T. Shimızu, T. Kawabata, M. Nakamura, Protective Effect Of A Novel Calcium Blocker, S– 312–D, On Ischemic Acute Renal Failure In Rat, The Journal of Pharmacology and Experintal Therapeutics, 255(2), (1990), 484–490.
43. [43] A. Başaran, K. Erol N. Başaran, Verapamil'in Karaciğer Rejenerasyonu ve Bazı Enzim Düzeylerine Etkisi, Tr J Of Med Sci, 15, (1991), 308–313.