EFFECTS OF CISPLATIN AND AMPHOTERICIN-B ON DNA ADDUCT FORMATION AND TOXICITY IN MALIGNANT GLIOMA AND NORMAL-TISSUES IN RAT

In an attempt to modify the cytotoxicity of cisplatin, amphotericin B (AmB) was given as pretreatment to BDIX rats with intracerebral BT4C g lioma implants. Ten animals given AmB 5 mg/kg i.p. followed by cisplat in 5 mg/kg i.p. displayed massive haematuria within 24 h after treatme nt and died a few days later. The antitumoral effect could not, theref ore, be evaluated. Histopathological examination of the kidneys showed extensive tubular necrosis. No signs of apoptotic cell death were fou nd using in situ end labelling with biotin-labelled nucleotides or wit h DNA integrity analysis in agarose gel electrophoresis. An immunohist ochemical method for analysis of cisplatin-DNA adducts was used to elu cidate the distribution of cisplatin in brain tumour, normal brain and kidney. Addition of AmB to cisplatin caused increased adduct formatio n in kidneys, particularly in tubular cells. It seems plausible that t he nephrotoxicity, at least in part, was mediated by increased levels of cisplatin-DNA adducts. Pretreatment with AmB did not have any obvio us effect on the formation of adducts in the cerebral cortex. The addu ct levels in the tumours from animals pretreated with AmB were not sig nificantly increased compared with those treated with cisplatin only. Thus, addition of AmB to cisplatin caused excessive nephrotoxicity sug gesting a decrease in the therapeutic ratio of cisplatin. (C) 1997 Pub lished by Elsevier Science Ltd.