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Cyclophosphamide Induces Hepatorenal Toxicity and Attenuation by 5-fluorouracil in Male Albino Rats

Rabia A M Yahya, Ahmed M. Attia, Mona A. Yehia, Azab Elsayed Azab, Karema El.M.Shkal

World Journal of Clinical Medicine Research 2(1); 10.31586/wjcmr.2022.455 - October 14, 2022

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Abstract

Background: Cyclophosphamide (CPA) induces acute inflammation of the urinary bladder, renal damage, and liver damage, thereby limiting its therapeutic use. Objectives: The present study aimed to evaluate the hepatorenal toxicity induced by cyclophosphamide and amelioration by 5-fluorouracil in male albino rats. Materials and Methods: Twenty-eight male adult rats were grouped randomly into four groups (n=5 for each group). Group I (control): Rats were injected with saline intraperitoneally and at a dose of 1.0 ml/kg b.w. for 14 days. Group II cyclophosphamide (CPA): Cyclophosphamide at a dose of 10 mg/kg day by day through i.p. to rats for 14 days. Group III Fluorouracil (5-FU): 5-Fluorouracil at a dose of 10 mg/kg day by day in saline was given through i.p. to rats for 14 days. Group IV (CPA+5-FU): Rats were given CPA followed by 5-FU at a dose of 10 mg/kg per day (day by day) through i.p. to rats for 14 days. At the end of the experimental period, rats were anesthetized using light ether. Blood samples were taken and prepared for biochemical measurements. Results: Serum total protein, albumin, and globulin concentration significantly reduced in animal groups that received cyclophosphamide. 5-FU and CPA combination reduced the changes in total protein, albumin, and globulin compared to CPA treated group. A significant increase in LDH serum concentration was found in CPA, 5-FU, and their combination-treated animals. The mean values of the combination of chemotherapy were above that in CPA followed by 5-FU treatment. Administration of CPA, 5-FU resulted in a significant increase in serum AST, ALT, ALP, and bilirubin compared to the control. Co-treatment 5-FU with CPA significantly attenuated the increase in serum AST, ALT, ALP, and bilirubin when compared to CPA – treated rats. Compared to controls, urea and creatinine levels were increased in CPA-treated rats, while uric acid was reduced in CPA, 5-FU, and their combination. The changes in urea and creatinine produced by the chemotherapy were restored when rats received CPA in combination with 5-FU. Conclusion: It could be concluded that the treatment of mammals with chemotherapy is associated with the production of free radicals that lead to hazardous alterations in biochemical parameters. However, 5-FU and CPA combination could produce a significant amelioration in most cases for these changes, and it may be considered as a potentially useful candidate in the combination chemotherapy with CPA to combat oxidative stress-mediated non-target organ injury even if it was not complete protection. Future work should consider combined chemotherapy regimens, as two or more mechanisms of action of chemotherapeutic drugs could be more powerful than one mechanism. Toxicological studies must be performed before using drugs as a combination before application. Further research is required on the toxicological impacts of drugs and pollutants mixtures.

Figure 1. Serum total protein concentration of rat treated with cyclophosphamide and/or 5-fluorouracil. Significance at P>0.05. CPA: cyclophosamide; 5-FU: Fluorouracil. a Comparison of control and other groups; b Comparison of CPA and other groups; c Comparison of 5-FU and other groups; d Comparison of CPA – 5-FU and other groups.

Figure 2. Serum albumin concentration of rat treated with cyclophosphamide and 5-fluorouracil and their combination. Significance at P>0.05. CPA: cyclophosamide; 5-FU: Fluorouracil. a Comparison of control and other groups; b Comparison of CPA and other groups; c Comparison of 5-FU and other groups; d Comparison of CPA–5-FU and other groups.

Figure 3. Serum glonulin concentration of rat treated with cyclophosphamide and/or 5-fluorouracil. Significance at P>0.05. CPA: cyclophosamide; 5-FU: Fluorouracil. a Comparison of control and other groups; b Comparison of CPA and other groups; c Comparison of 5-FU and other groups; d Comparison of CPA – 5-FU and other groups.

Figure 4. Serum LDH activity of rat treated with cyclophosphamide and/or 5-fluorouracil. Significance at P>0.05. CPA: cyclophosamide; 5-FU: Fluorouracil. a Comparison of control and other groups; b Comparison of CPA and other groups; c Comparison of 5-FU and other groups; d Comparison of CPA – 5-FU and other groups.

Figure 5. Serum ALT activity of rat treated with cyclophosphamide and 5-fluorouracil and their combination. Significance at P>0.05. CPA: cyclophosamide; 5-FU: Fluorouracil. a Comparison of control and other groups; b Comparison of CPA and other groups; c Comparison of 5-FU and other groups; d Comparison of CPA–5-FU and other groups.

Figure 6. Serum AST activity of rat treated with cyclophosphamide and/or 5-fluorouracil. Significance at P>0.05. CPA: cyclophosamide; 5-FU: Fluorouracil. a Comparison of control and other groups; b Comparison of CPA and other groups; c Comparison of 5-FU and other groups; d Comparison of CPA – 5-FU and other groups.

Figure 7. Serum ALP activity of rat treated with cyclophosphamide and 5-fluorouracil and their combination. Significance at P>0.05. CPA: cyclophosamide; 5-FU: Fluorouracil. a Comparison of control and other groups; b Comparison of CPA and other groups; c Comparison of 5-FU and other groups; d Comparison of CPA–5-FU and other groups.

Figure 8. Serum total bilirubin of rat treated with cyclophosphamide and 5-fluorouracil and their combination. Significance at P>0.05. CPA: cyclophosamide; 5-FU: Fluorouracil. a Comparison of control and other groups; b Comparison of CPA and other groups; c Comparison of 5-FU and other groups; d Comparison of CPA–5-FU and other groups.

Figure 9. Serum urea concentration of rat treated with cyclophosphamide and/or 5-fluorouracil. Significance at P>0.05. CPA: cyclophosamide; 5-FU: Fluorouracil. a Comparison of control and other groups; b Comparison of CPA and other groups; c Comparison of 5-FU and other groups; d Comparison of CPA – 5-FU and other groups.

Figure 10. Serum creatinine concentration of rat treated with cyclophosphamide and 5-fluorouracil and their combination. Significance at P>0.05. CPA: cyclophosamide; 5-FU: Fluorouracil. a Comparison of control and other groups; b Comparison of CPA and other groups; c Comparison of 5-FU and other groups; d Comparison of CPA–5-FU and other groups.

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Open Access Article

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5-Fluorouracil Ameliorates the Hematotoxicity Induced by Cyclophosphamide in Male Albino Rats

Rabia A M Yahya, Azab Elsayed Azab, Ahmed M. Attia, Mona A. Yehia, Karema El.M.Shkal

Universal Journal of Pharmacy and Pharmacology 1(1); 10.31586/ujpp.2022.453 - September 27, 2022

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Abstract

Background: Cyclophosphamide (CPA) is a drug with a wide spectrum of clinical uses. Its effectiveness in the treatment of cancer (acute and chronic leukemias, lymphoma, and multiple myeloma) and non-malignant diseases such as rheumatoid arthritis and vasculitis has been well established. Objectives: The present investigation aimed to study the effect of a sub-lethal dose of the cyclophosphamide, 5-FU combination of 5-FU, and CPA on haematological parameters in the albino rats. Materials and Methods: Twenty-eight male adults were grouped randomly into four groups (n=5 in each group). Group I (control): Rats were injected with saline intraperitoneally at a dose of 1.0 ml/kg b.w. for 14 days. Group II cyclophosphamide (CPA): Cyclophosphamide at a dose of 10 mg/kg day by day through i.p. to rats for 14 days. Group III Fluorouracil (5-FU): 5-Fluorouracil at a dose of 10 mg/kg day by day in saline was given through i.p. to rats for 14 days. Group IV (CPA+5-FU): Rats were given CPA followed by 5-FU at a dose of 10 mg/kg per day (day by day) through i.p. to rats for 14 days. At the end of the experimental period, rats were anesthetized using light ether. Blood samples were taken for hematological evaluation. Results: White blood cells, hemoglobin content and red blood cell counts were significantly decline in rats treated with individual treatment with CPA and 5-FU in comparison to the control group, while the Combination antagonize the changes produced by CPA in hemoglobin and red blood cell counts. Intraperitoneal individual treatment with CPA and 5-FU in rats caused a significant reduction in the hematocrit and platelet. The reductions in these measured hematological parameters were also significantly and slightly ameliorated when the animals were given a combination of CPA and 5-FU. Cyclophosphamide and 5-FU individually reduced lymphocytes, neutrophils, eosinophils, and monocytes; while the combination of CPA and 5-FU antagonized these changes compared to CPA treated group. Conclusion: It could be concluded that the treatment of mammals with chemotherapy is associated with the production of free radicals that lead to hazardous alterations in hematological parameters. However, 5-FU and CPA combination could produce a significant amelioration in most cases for these changes. Future work should consider combined chemotherapy regimens, as two or more mechanisms of action of chemotherapeutic drugs could be more powerful than one mechanism. Using cyclophosphamide and 5-fluorouracil in combination may reduce cyclophosphamide’s side effects when given individually.

Figure 1. WBCs count (x103/µL) of rat treated with cyclophosphamide and/or 5-fluorouracil. Significance at P>0.05. CPA: cyclophosamide; 5-FU: Fluorouracil. a Comparison of control and other groups; b Comparison of CPA and other groups.

Figure 2. RBCs count (106/µL) of rat treated with cyclophosphamide and 5-fluorouracil and their combination. Significance at P>0.05. CPA: cyclophosamide; 5-FU: Fluorouracil. a Comparison of control and other groups; b Comparison of CPA and other groups; c Comparison of 5-FU and other groups; d Comparison of CPA–5-FU and other groups.

Figure 3. Hemoglobin content (g/dl) of rat treated with cyclophosphamide and/or 5-fluorouracil. Significance at P>0.05. CPA: cyclophosamide; 5-FU: Fluorouracil. a Comparison of control and other groups; b Comparison of CPA and other groups; c Comparison of 5-FU and other groups; d Comparison of CPA – 5-FU and other groups.

Figure 4. Hematocrit value (%) of rat treated with cyclophosphamide and/or 5-fluorouracil. Significance at P>0.05. CPA: cyclophosamide; 5-FU: Fluorouracil. a Comparison of control and other groups; b Comparison of CPA and other groups; c Comparison of 5-FU and other groups; d Comparison of CPA – 5-FU and other groups.

Figure 5. Platelets count (103/μl) of rat treated with cyclophosphamide and/or 5-fluorouracil. Significance at P>0.05. CPA: cyclophosamide; 5-FU: Fluorouracil. a Comparison of control and other groups; b Comparison of CPA and other groups; c Comparison of 5-FU and other groups; d Comparison of CPA – 5-FU and other groups.

Figure 6. Lymphocytes count (x103/µl) of rat treated with cyclophosphamide and/or 5-fluorouracil. Significance at P>0.05. CPA: cyclophosamide; 5-FU: Fluorouracil. a Comparison of control and other groups; b Comparison of CPA and other groups; c Comparison of 5-FU and other groups; d Comparison of CPA – 5-FU and other groups.

Figure 7. Neutrophils count (x103/µl) of rat treated with cyclophosphamide and/or 5-fluorouracil. Significance at P>0.05. CPA: cyclophosamide; 5-FU: Fluorouracil. a Comparison of control and other groups; b Comparison of CPA and other groups; c Comparison of 5-FU and other groups; d Comparison of CPA – 5-FU and other groups.

Figure 8. Eosinophils count (x103/µl) of rat treated with cyclophosphamide and/or 5-fluorouracil. Significance at P>0.05. CPA: cyclophosamide; 5-FU: Fluorouracil. a Comparison of control and other groups; b Comparison of CPA and other groups; c Comparison of 5-FU and other groups; d Comparison of CPA – 5-FU and other groups.

Figure 9. Monocytes count (x103/µl) of rat treated with cyclophosphamide and/or 5-fluorouracil. Significance at P>0.05. CPA: cyclophosamide; 5-FU: Fluorouracil. a Comparison of control and other groups; b Comparison of CPA and other groups; c Comparison of 5-FU and other groups; d Comparison of CPA – 5-FU and other groups.

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