Myelosuppression and Oxidative Stress Induced by Cyclophosphamide in Rats: The Protective Role of Selenium

Öz

Aim of this study is to detect the protective role of selenium (Se) against bone marrow and blood toxicity in CP-induced hematoxicity model. We categorized the rats into 6 groups of 7 animals in each group (control; 150 mg/kg CP; 0.5 mg/kg Se; 1 mg/kg Se; 150+0.5 mg/kg CP+Se; 150+1 mg/kg CP+Se). Se injections started 5 days before the CP injections and carried on until the end of the experiment (6^th day) for the groups to which CP was injected together with Se. CP was applied as a single dose before anesthesia. For that reason, on the 7^th day, blood was taken with cardiac puncture and bone marrow was taken by flushing the femur. Peripheral blood cells and bone marrow nucleated cells were counted on a cell counter. Intraperitoneal CP injection was found to reduce the number of leukocytes by 317%, thrombocyte by 36% and bone marrow nucleated cells by 481% compared to the control group. In the groups where CP was given after 0.5 and 1 mg/kg Se, numbers of leukocyte, thrombocyte and bone marrow nucleated cells were considerably improved compared to the group to which CP was given only (p<0.001). Results show that 1 mg/kg Se has a better protection than 0.5 mg/kg against CP associated hematoxicity and myelosuppression. Our results also imply that the doses of Se could be adjusted according to enhance in CP dose so as to gain a stronger protective effect. We believe there is a need of further studies in which different doses of Se will be used against CP induced hematoxicity. Se can provide protection against CP-induced myelosupression and lipid peroxidation.

Anahtar Kelimeler

• Cyclophosphamide,hematoxicity,selenium,myelosupression,lipid peroxidation

Sıçanlarda Siklofosfamid'in Neden Olduğu Miyelosupresyon ve Oksidatif Stres: Selenyumun Koruyucu Rolü

Öz

Bu çalışmanın amacı, selenyumun (Se), CP kaynaklı hematoksisite modelinde kemik iliği ve kan toksisitesine karşı koruyucu rolünü tespit etmekti. Her grupta sıçanları 7 hayvandan oluşan 6 gruba ayırdık (kontrol; 150 mg/kg CP; 0,5 mg/kg Se; 1 mg/kg Se; 150+0,5 mg/kg CP+Se; 150+1 mg/kg). CP+Se). Se enjeksiyonları, CP enjeksiyonlarından 5 gün önce başlamış ve Se ile birlikte CP enjekte edilen gruplar için deneyin sonuna (6. gün) kadar devam etmiştir. CP anestezi öncesi tek doz olarak uygulandı. Bu nedenle 7. günde kardiyak delinme ile kan alındı ve femur yıkanarak kemik iliği alındı. Periferik kan hücreleri ve kemik iliği çekirdekli hücreler, bir hücre sayacında sayıldı. İntraperitoneal CP enjeksiyonunun lökosit sayısını %317, trombositi %36 ve kemik iliği çekirdekli hücreleri %481 azalttığı bulundu. CP' nin 0,5 ve 1 mg/kg Se'den sonra verildiği gruplarda, sadece CP verilen gruba kıyasla lökosit, trombosit ve kemik iliği çekirdekli hücrelerin sayısı önemli ölçüde artmıştır (p<0.001). Sonuçlar, 1 mg/kg Se'nin, CP ile ilişkili hematoksisite ve miyelosupresyona karşı 0,5 mg / kg'dan daha iyi bir korumaya sahip olduğunu göstermektedir. Sonuçlarımız ayrıca, Se dozlarının daha güçlü bir koruyucu etki elde etmek için CP dozundaki artışa göre ayarlanabileceği anlamına gelir. CP'nin neden olduğu hematoksisiteye karşı farklı Se dozlarının kullanılacağı konusunda daha fazla çalışmaya ihtiyaç olduğuna inanıyoruz. Se, CP kaynaklı miyelosupresyon ve lipit peroksidasyonuna karşı koruma sağlayabilir.

Anahtar Kelimeler

• Siklofosfamid,Hematoksisite,Selenyum,Miyelosupresyon,Lipit peroksidasyonu

Kaynakça

1. [1] Kumar, K.B., Kuttan, R., Chemoprotective activity of an extract of Phyllanthus amarus against cyclophosphamide-induced toxicity in mice, Phytomedicine, 12, 494-500, 2004.
2. [2] Senthilkumar, S., Devaki, T., Manohar, B.M., Babu, M.S., Effect of squalene on cyclophosphamide-induced toxicity, Clinica Chimitica Acta, 364(1-2), 335-42, 2006.
3. [3] Kawabata, T.T., Chapman, M.Y., Kim, D.H., Stevens, W.D., Holsapple, M.P., Mechanism of in vitro immunu suppression by hepatocyte generated cyclophosphamide metabolites and 4-Hydroxi cyclophosphamide, Biochemical Pharmacology, 40(5), 927- 935, 1990.
4. [4] Kehrer, J.P., Biswal, S.S., The molecular effects of acrolein, Toxicological Sciences, 57(1), 6-15, 2000.
5. [5] Sabitha, K.E., Shyamaladevi, C.S., Oxidant and antioxidant activity changes in patients with oral cancer and treated with radiotherapy, Oral Oncology, 35(3), 273-7, 1999. [6] Akkuş, İ., Serbest radikaller ve fizyopatolojik etkileri. Mimoza Yayınları, Konya, 1995.
6. [7] Byers, T., Perry, G., Dietary carotenes, vitamin C, and vitamin E as protective antioxidants in human cancers, Annual Review of Nutrition, 12, 139-159, 1992.
7. [8] İşcan, M., Çoban, T., Normal veneoplastik meme dokusunda antioksidan enzimler. Klinik Gelişim, 11, 392-395, 1998.
8. [9] Kohrle, J., Jakob, F., Contempre, B., Dumont, J.E., Selenium, the thyroid, and the endocrine system, Endocrine Reviews, 26:944-84, 2005.

9. [10] Brown, K.M.., Arthur, J.R., Selenium, selenoproteins and human health: a review, Public Health Nutrition, 4, 593-599, 2001.
10. [11] Rayman, M.P., The importance of selenium to human health, Lancet, 356(9225), 233-41, 2000.
11. [12] Ilio, C.D., Boccio, G.D., Casaccia, R., Aceto, A. Giacomo, F., Federici, G., Selenium level and glutathione-depent enzyme activities in normal and neoplastic human lung tissues, Carcinogenesis, 8(2), 281-284, 1987.
12. [13] Dai, J., Weinberg, R.S., Waxman, S., Jing, Y., Malignant cells can be sensitized to undergo growth inhibition and apoptosis by arsenic trioxide through modulation of the glutathione redox system, American Society of Hematology, 93(1),268-277, 1999.
13. [14] Ayhanci, A., Gunes, S., Sahinturk, V., Appak, S., Uyar, R., Cengiz, M., Altuner, Y., Yaman, S., Seleno L-methionine acts on cyclophosphamide-induced kidney toxicity, Biological Trace Element Research, 136, 171–179, 2010.
14. [15] Ayhanci, A., Uyar, R., Aral, E., Kabader, S., Appak, S., Protective effect of zinc on cyclophosphamide-induced hematoxicity and urotoxicity, Biological Trace Element Research, 126, 186–193, 2008.
15. [16] Esterbauer, H., Cheeseman, K. H., Determination of aldehydic lipid peroxidation products: malonaldehyde and 4-hydroxynonenal, Methods in Enzymology, 186, 407–42, 1990.
16. [17] Liang, J., Huang, M., Duan, W., Yu, X. Q., Zhou, S., Design of new oxazaphosphorine anticancer drugs, Current Pharmaceutical Design, 13, 963–978, 2007.
17. [18] George, K.S., Rajesh, R., Sunil, K.S., Sulekha, B., Balaram, P., A polyherbal ayurvedic drug—Indukantha Ghritham as an adjuvant to cancer chemotherapy via immunomodulation, Immunobiology, 213,641–649, 2008.
18. [19] Fraiser, L.H., Kanekal, S., Kehrer, J.P., Cyclophosphamide toxicity: characterizing and avoiding the problem, Drugs, 42,781–795, 1991.
19. [20] Schuurman, H.J., Smith, H.T., Cozzi, E., Tolerability of cyclophosphamide and methotrexate induction immunosuppression in nonhuman primates, Toxicology, 213, 1–12, 2005.
20. [21] Moore, F.R., Urda, G. A., Krishna, G., Theiss, J. C., An invivo/invitro method for assessing micronucleus and chromosome aberration induction in rat bone morrow and spleen. 1. Studies with cyclophosphamide, Mutataion Research/Environmental Mutagenesis and Related Subjects, 335(2), 191-199, 1995.
21. [22] Trasler, J.M., Hales, B.F., Robaire, B., A time-course study of chronic paternal cyclophosphamide treatment in rats: effects on pregnancy outcome and themalere productive and hematologic systems, Biology of Reproduction, 37(2),317-26, 1987.
22. [23] Cengiz, M., Hematoprotective effect of boron on cyclophosphamide toxicity in rats, Cellular and Molecular Biology (Noisy le Grand), 64(5),62-65, 2018.
23. [24] Ayhanci, A., Yaman, S., Appak, S., Gunes, S., Hematoprotective effect of seleno-L-methionine on cyclophosphamide toxicity in rats, Drug and Chemical Toxicology, 32(4), 424-428, 2009.
24. [25] Korkmaz, A., Topal, T., Oter, S., Pathophysiological aspects of cyclophosphamide and ifosfamide induced hemorrhagic cystitis; implication of reactive oxygen and nitrogen species as well as PARP activation, Cell Biology and Toxicology, 23, 303–312, 2007.
25. [26] Spallholz, J.E., Use of selenium to prevent and treat cancer in the new millennium, Journal of Korean Association of Cancer Prevention, 8:9–23, 2003.
26. [27] Olas, B., Wachowicz, B., Selenium in the cytotoxicity of cisplatin, Postępy Higieny i Medycyny Doświadczalnej, 51, 95–108, 1997.
27. [28] Weijl, N.I., Elsendoorn, T.J., Lentjes, E.G., Hopman, G.D., Wipkink-Bakker, A., Zwinderman, A.H., Supplementation with antioxidant micronutrients and chemotherapy-induced toxicity in cancer patients treated with cisplatin-based chemotherapy: a randomised, double- blind, placebo-controlled study, European Journal of Cancer, 40, 1713–1723, 2004.
28. [29] Sieja, K., Talerczyk, M., Selenium as an element in the treatment of ovarian cancer in women receiving chemotherapy, Gynecologic Oncology, 93, 320–327, 2004.
29. [30] Zeng, H., Combs, J.G.F., Selenium as an anticancer nutrient: roles in cell proliferation and tumor cell invasion, Journal of Nutritional Biochemistry, 19, 1–7, 2008.
30. [31] Stankiewicz, A., Skrzydlewska, E., Amifostine Antioxidant Effect on Serum of Rats Treated with Cyclophosphodamide, Polish Journal of Environmental Studies, 14(3), 341-346, 2005.