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  • 1
    Electronic Resource
    Electronic Resource
    CCNU-Adriamycin association induces earlier and more severe nephropathy in rats (1988)
    Springer
    Archives of toxicology 61 (1988), S. 282-291 
    Details
    ISSN: 1432-0738
    Keywords: Adriamycin ; CCNU ; Nephrotoxicity ; Hepatotoxicity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Adriamycin (ADR) has a broad spectrum of antitumoral activity but is ineffective against human brain tumors. However, such tumors can be sensitive to a combination of adriamycin and lipophilic antineoplastic agents such as the nitrosoureas. CCNU, a nitrosourea, induces cholestasis in the rat and ADR is predominantly excreted via the biliary route. We decided to investigate the effect of CCNU on the nephrotic syndrome induced by ADR. Female Wistar rats were injected with a single dose of 10 mg/kg ADR and 24 h later were force fed 20 mg/kg CCNU in a single dose. Animals were sacrificed 4, 8, 15, 21, 28 or 60 days after the injection of ADR. A high rate of fatality (60%) occurred after the 21st day of treatment. Biological changes (alkaline phosphatase, SGPT, bilirubin) and ultrastructural studies showed that CCNU and CCNU+ADR induced the same degree of cholestasis. With the administered dose, CCNU is not nephrotoxic, ADR induces a nephrotic syndrome and ADR+CCNU appeared more nephrotoxic. With ADR, visceral epithelial foot process fusion was seen on day 15 and tubulo-interstitial lesions and glomerulosclerosis on day 60. With ADR+CCNU fusion of the foot process was seen on day 4, glomerular vacuolation on day 8, tubulo-interstitial alterations on day 15 and glomerulosclerosis on day 60. For both ADR and ADR+CCNU wrinkling and thickening of the basement membrane of proximal tubular cells were seen on day 60. Lipid mesangial overload was seen with ADR and was more intense with ADR+CCNU on day 60. CCNU hepatoxicity modifies the excretion of ADR and the predominantly renal excretion of ADR seems to induce earlier renal alterations in ADR+CCNU-treated rats. This study supports the concept that lipid mesangial overload may play an important role in chronic progressive glomerulosclerosis and thus the ADR+CCNU combination appears to be an interesting model in which to study these relationships.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00364851
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  • 2
    Electronic Resource
    Electronic Resource
    Renal toxicity of the antitumor drug N2-methyl-9-hydroxyellipticinium acetate in the wistar rat (1988)
    Springer
    Archives of toxicology 61 (1988), S. 292-297 
    Details
    ISSN: 1432-0738
    Keywords: Nephrotoxicity ; Cytostatic drug ; Celiptium ; Rat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Celiptium (N2-methyl-9-hydroxy-ellipticinium) is an antitumoral agent used to treat bone metastases from breast carcinomas. This new drug appeared to be of great interest because of the absence of hepato-or myelotoxicity. Three different investigators recently mentioned cases of celiptium-induced renal failure. We therefore undertook a study of renal function and morphology in female Wistar rats. Two single i.v. doses (10 or 20 mg/kg) were administered and animals were sacrificed 4, 8, 15, 28 and 60 days after injection. One group of rats received multiple doses, 5 mg/kg/week for 8 weeks. No mortality was observed. With the 10 mg/kg single dose creatinine clearance (Ccr) and urinary enzymes did not change, and tubular lesions were rare. With the 20 mg/kg single dose CCr decreased on day 4 and returned to normal on day 28. Urinary enzyme excretion (AAP, NAG, γGT) increased. Renal lesions were diffuse with tubular necrosis, luminal dilation and later (day 28) interstitial cellular infiltration. These lesions persisted on day 60 and appeared to be irreversible. Ultrastructural studies showed numerous large fat droplets in proximal tubular cells. Glycerol concentrations in renal cortex homogenates were increased while phospholipids are slightly decreased. With 5 mg/kg every week (multiple doses) Ccr decreased and tubular lesions similar to the observed with the 20 mg/kg single dose were seen. Thus celiptium induced dose-dependent nephrotoxicity in rats with prolonged tubular alterations. Since it has been shown that renal tubular cells metabolized celiptium in vitro into electrophilic intermediates, we suggest that free radicals and quinone derivatives may contribute to peroxidation of unsaturated fatty acids and play a role in the nephrotoxicity of the drug.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00364852
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  • 3
    Electronic Resource
    Electronic Resource
    Erratum (1988)
    Springer
    Archives of toxicology 61 (1988), S. 506-508 
    Details
    ISSN: 1432-0738
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00293700
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    Paper (German National Licenses)
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  • 4
    Electronic Resource
    Electronic Resource
    Celiptium neprhotoxicity generated oxidative lipid damage in brush-border membranes of rat renal cortex
    Amsterdam : Elsevier
    Free Radical Biology and Medicine 9 (1990), S. 121 
    Details
    ISSN: 0891-5849
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Type of Medium: Electronic Resource
    URL: http://linkinghub.elsevier.com/retrieve/pii/0891-5849(90)90605-I
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  • 5
    Electronic Resource
    Electronic Resource
    Evidence for 4-hydroxyalkenals in rat renal cortex peroxidized by N^2-methyl-9-hydroxyellipticinium acetate or celiptium^(R)
    Amsterdam : Elsevier
    Biochimica et Biophysica Acta (BBA)/Lipids and Lipid Metabolism 1046 (1990), S. 294-300 
    Details
    ISSN: 0005-2760
    Keywords: 4-Hydroxyalkenal ; Antitumor agent ; Celiptium ; Lipid peroxidation ; Phosphatidylethanolamine
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Biology , Chemistry and Pharmacology , Medicine , Physics
    Type of Medium: Electronic Resource
    URL: http://linkinghub.elsevier.com/retrieve/pii/0005-2760(90)90244-R
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  • 6
    Electronic Resource
    Electronic Resource
    The hepatotoxicity of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) in rats (1988)
    Springer
    Cancer chemotherapy and pharmacology 22 (1988), S. 153-162 
    Details
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A few cases of liver involvement have been reported in patients receiving treatment with the antineoplastic nitrosourea CCNU. A single oral dose of 20 or 50 mg/kg CCNU in female Wistar rats induced an important increase in transaminases between day 2 and day 6, followed by a second, moderate increase between day 21 and day 28. Alkaline phosphatases and conjugated hyperbilirubinemia (threefold-increase) were noted for the two doses and were greater for the highest dose. Histological and ultrastructural studies disclosed hepatic lesions of two types: during the first phase of transaminase increase, inflammation of the portal tracts; during the second phase marked dilation of bile canaliculi and numerous filamentous bundles distributed at random throughout the liver cell cytoplasm like normal microtubules. Thus, CCNU induced pericholangitis and intrahepatic cholestasis with microtubular abnormalities. The long-term evolution of hepatic alterations revealed that in the 3rd month after a single oral dose of 20 mg/kg CCNU, lesions were persistent but stable; no reversibility was observed in the 3rd month after 50 mg/kg CCNU, and evolution towards cholangiolysis and biliary cirrhosis was noted. We suggest that CCNU causes a bimodal hepatotoxicity in rats: an early and prolonged ductal injury and a delayed anti-liver cell microtubule toxicity.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00257314
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