الفهرس 
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Abstract
Doxorubicin (Dox) is one of the most commonly used anti-cancer drugs. It is used for treatment of several adult and pediatric cancers, such as leukemia, lymphomas, many solid tumors, breast cancer, soft tissue sarcomas and many other cancers. Unfortunately, many studies elucidated that Dox causes a major morbidity and mortality, because of its complex pathogenesis. Increased oxidative stress and an antioxidant deficit have been suggested to play a major role in Dox-induced toxicity. The present study aims to assess the deleterious effects of Dox on liver, kidney and heart of Wistar rats as well as the preventive effects of S. versicolor water-derivative extract and organic fractions against these toxic effects. To achieve this aim, sixty adult male rats were allocated into 6 groups; the first group was normal control group, the second was Dox-treated group, and the other four groups were respectively treated with water-derivative extract and ethyl acetate, n-butanol and petroleum ether fractions at dose level of 10 mg/kg body weight.
The present results revealed that at the end of experiment, the body weight gain of the Dox+ petroleum ether fraction group was the highest one (73.30 g) followed by control, Dox+ethyl acetate fraction, Dox+water-derivative extract and Dox+n-butanol fraction groups (67.28, 61.67, 58.50 and 38.66 g respectively). The lowest body weight gain was obtained in Dox-treated group that recorded 29.00 g.
The hematological results indicated that Dox-treated group exhibited a significant decrease in RBCs and platelets counts as well as Hb content. The total leukocyte, neutrophils and monocytes counts were significantly decreased while the basophils, eosinophils and lymphocytes counts were a significantly increased in Dox-treated group. The administration of water-derivative extract and organic fractions to Dox-treated rats caused a significant amelioration of the abnormal values of these hematological parameters. The petroleum ether fraction seemed to be the most potent in improving the deterioration in the total leukocyte count and differential leukocyte count caused by Dox injection.
Regarding liver function, serum total bilirubin level and the activities of ASAT, ALAT and GGT showed a significant increase while the serum albumin level exhibited a significant decrease in Dox-treated group as compared to control group. The treatment of Dox group with petroleum ether fraction was the best one in decreasing the elevated total bilirubin level and ASAT, ALAT and GGT activities while the treatment of Dox group with n-butanol fraction was the worst one where it showed adverse effects.
Concerning lipid profile, serum TC, TG, LDL-C and vLDL levels exhibited a significant increase while serum HDL-C level showed a significant decrease in Dox-treated group as compared to the control group. The administration of water-derivative extract and organic fractions to Dox-treated rats caused a significant amelioration of the deteriorated serum lipid profile.
With regard to kidney function, the Dox-treated and Dox+n-butanol fraction groups showed a deleterious increasing effect on serum urea level as compared with normal control group while Dox-treated group is the only group that exhibited a significant elevation in serum creatinine level as compared with the normal control group. The petroleum ether fraction was the most potent in decreasing the elevated levels of serum urea and creatinine levels of Dox-treated rats.
The cardiac enzymes LDH and CK-MB showed the highest activity in Dox-treated group and the lowest activity in Dox+petroleum ether fraction group. The highest CVR-F1 was reported in Dox-treated group and CVR-F2 in Dox+n-butanol fraction group. Petroleum ether fraction seemed to be the most effective in counteracting the deleterious effects of Dox on serum urea, creatinine, CVR-F1 and CVR-F2.
Alpha fetoprotein and sialic acid levels and arginase activity as tumor markers showed highest values in Dox-treated group. The lowest values of them were recorded in Dox+petroleum ether fraction group. Therefore, petroleum ether fraction was the most potent in restoring the elevated serum tumor markers to their normal values.
Concerning the oxidative stress and the antioxidant defense system, LPx showed the highest values in the liver, kidney and heart tissues of Dox+n-butanol fraction group. LPx was significantly elevated in Dox-treated rats. On the other hand, Dox+petroleum ether fraction group exhibited the most potent ameliorating effects in decreasing the elevated LPx as compared Dox-treated group. Antioxidant defense, represented by GSH content and GST, GPx and SOD activities, was deleteriously suppressed in liver, kidney and heart of Dox-treated rats and Dox+n-butanol fraction group. Generally, the treatment with water-derived extract and organic fractions, except for n-butanol, successfully counteracted the deteriorated effects of Dox on the anti-oxidant defense system.
Histopathological alterations reported that the liver of Dox-treated rats exhibited congestion of main blood vessels and sinusoidal spaces and hemorrhages in-between the neoplastic areas in association with multifocal hepatocytic necrosis nearby neoplastic growths. The Dox+ethyl acetate fraction and petroleum ether fraction groups showed a marked amelioration of liver histological architecture and integrity but still exhibited congestion of sinusoidal spaces and mild focal vacuolar degeneration. The kidney of Dox-treated group exhibited moderate diffuse cloudy swelling of tubular epithelial cells with some cast formation and moderate multifocal tubular necrosis. The Dox+water-derivative extract showed only multifocal glomerulo-tubular necrosis. The Dox-administered rats treated with n-butanol and petroleum ether fractions of S. versicolor, respectively showed distinctive areas of cloudy swelling of tubular epithelial cells with moderate multifocal tubular necrosis leaving empty spaces and distinct focal areas of coagulative tubular necrosis. The myocardium of Dox-treated rats showed multifocal swelling of myocardial cells with focal areas of Zinker’s necrosi and mild swelling of some myofibers. Dox+water-derivative extract, Dox+ethyl acetate fraction and Dox+petroleum ether fraction showed recovering of the detected lesions, where they recorded normal histological structure and integrity.
Overall, it can be concluded that doxorubicin induced toxicity in liver, kidney and heart of male Wistar albino rats via stimulation of lipid peroxidation and suppression of antioxidant defense system. The co-treatment with S. versicolor water derivative extract and organic fractions except for n-butanol fraction potentially improved liver, kidney and heart function and histological integrity in Dox-administered rats via suppression of oxidative stress and enhancement of the antioxidant defense system. Moreover, petroleum ether fraction appeared to produce the most potent ameliorating effects while the co-treatment with n-butanol fraction was the worst one. Thus, the present study recommends that more studies will be needed to explain why extract and fractions of S. versicolor have different effects on Dox-toxicity.