studia universitatis babeÅ-bolyai biologia 2

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STUDIA UNIVERSITATIS BABEŞ-BOLYAI, BIOLOGIA, XLV, 2, 2000 HISTOLOGICAL AND ULTRASTRUCTURAL INJURIES IN THE RAT KIDNEY AFTER EXPOSURE TO CISPLATIN CRISTINA PAŞCA * , VIOREL MICLĂUŞ ** , CONSTANTIN CRĂCIUN*, ERIKA KIS*, VICTORIA DOINA SANDU*, VERONICA CRĂCIUN*, IONEL PAPUC** and CRISTIAN MUNTEANU *** SUMMARY. – Cisplatin, a platinum compound, is an alkylating agent with a marked antitumour activity, that has been extensively and successfully applied in the chemotherapy of several types of cancer (testicular, ovarian, pulmonary etc). Unfortunately, it has a significant hematologic and nonhematologic toxicity, especially nephrotoxicity. The tissue injury and repair in the rat kidney induced by this anticancer drug are still incompletely known; therefore, we tried to emphasise the histological and ultrastructural modifications induced by some therapeutic doses of Cisplatin on the rat kidney. Our researches demonstrated that the lesions were very grave, affected wide areas and progressively and significantly grew worse during the experiment. They consisted of the appearance of a marked swelling of the renal tubules, especially between the cortex and medulla, a distension of the epithelial cells, the cytoplasm of which appeared homogeneous and in some areas the epithelium was atrophied or detached. In addition, it could be noticed a granular material inside the renal tubules (because of the necrosis processes of the epithelial cells), a proliferation of mesangial and endothelial cells, an accumulation of certain circulating elements (polymorphonuclears, monocytes, lymphocytes) in the capillary lumen. The mesangial and monocytic interposition determined the parietal thickening and the striking "double outline" aspect of the basement membrane. Electron microscopy studies showed that Cisplatin induced grave nuclear alterations, a complete vacuolisation of the apical cytoplasm, intracellular lysis, while the mitochondria were swollen and had a rarefied matrix. Many epithelial cells in the uriniferous tubules had a seriously affected brush border, the microvilli being swollen and destroyed here and there, and the basal infoldings appeared hypertrophied. An increase of the mesangial matrix, with an obvious expansion in the capillary loops, determined the "double outline" aspect of the basement membrane which was found in light microscopy investigations. Besides, a pronounced cellularity of the glomeruli appeared, which was due to mesangial cell proliferation and especially to monocytic infiltration. Monocytes appeared in the mesangial zone, between the basement membrane and the endothelium along with mesangial cells, or in the lumen of some capillaries. Deposits of granular structure were found in the subendothelial area. * Babeş-Bolyai University, Department of Zoology, 3400 Cluj-Napoca, Romania. E-mail: cpasca@biolog.ubbcluj.ro ** University of Agricultural Sciences and Veterinary Medicine, Department of Histology, 3400 Cluj-Napoca, Romania *** Elementary School Nr. 17, 3400 Cluj-Napoca, Romania
C. PAŞCA et al. Cisplatin (Platinol, cis-DDP) is a platinum compound belonging to the alkylating agents, successfully applied in the chemotherapy of several types of cancer. The antineoplasic activity is generally believed to result from the interaction of the drug with the DNA in the tumour cells, this interaction leading to the formation of different types of adducts through the reaction of the bifunctional platinum compound with N7 atoms of the nucleobases guanine and adenine. The major adducts are intrastrand cross-links formed by the binding of cis-DDP on two neighbouring guanines, on adenine and guanine, and on two guanines separated by one or more nucleobases. Other types of adducts formed are the interstrand crosslink on two guanines and monofunctionally bound cis-DDP. Inside cells, cis-DDP can form DNA-protein cross-links [6-8]. Cisplatin has a significant hematologic and nonhematologic toxicity, especially nephrotoxicity. The histological and ultrastructural modifications induced by this anticancer drug on the rat kidney are still incompletely known; therefore, our investigations tried to emphasise these aspects in concordance with the moment of the sacrification after the administration of some therapeutic doses. Material and methods. Our experiments were carried out with the following five groups of healthy adult male Wistar rats, weighing 190 + 10 g and maintained under bioclimatic laboratory conditions, with no food for 18 hours before the treatment, but having water ad libitum: -group U – untreated (control) group; -group C 1 , C 2 , C 3 and C 4 treated i.v. with 20 mg Cisplatin /m 2 body surface/day, for three days, and sacrificed 24 hours, 4, 11 and 18 days after the treatment. The animals were not fed for 18 hours before the sacrification. Having sacrificed the animals, we took fragments from the kidney. For microscopic examination the fragments were fixed in 10% neutral formol, processed by the paraffin technique and the sections of 6 µm were stained by the hematoxylin-eosin, Masson-Goldner trichrome and PAS methods [12]. For ultrastructural investigations fragments of kidney were prefixed in 2.7% glutaraldehyde solution and postfixed in 2% osmic acid solution. The fragments were dehydrated in acetone and then embedded in Vestopal W. The ultrathin sections were obtained using an LKB III ultramicrotome and were contrasted with uranyl acetate. Examination of the sections were performed in a TESLA-BS-500 electron microscope [1, 10, 13]. On the stained and contrasted sections we studied, by light and electron microscopic examinations, the histological and ultrastructural modifications induced by this anticancer drug in concordance with the moment of the sacrification. Results and discussion. The light and electron microscopy investigations of the kidney sections showed the appearance of some significant modifications which seemed to be in concordance with the moment of the sacrification. 58
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ANUL XLV 2000 S T U D I A UNIVERSIT
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