Effects of amifostine on cisplatin induced DNA adduct formation and toxicity in malignant glioma and normal tissues in rat

The chemoprotective effect of amifostine (WR2721) was studied in a BDIX rat model with intracerebral BT4C glioma implants. Twenty-one rats were given cisplatin 5 mg/kg i.p., 21 were given amifostine 200 mg/kg i.p. + cisplatin 5 mg/kg i.p. Ten rats served as untreated controls. An immunohistochemical method for analysis of cisplatin-DNA adducts was used to elucidate the add uct formation in tumor, normal brain and kidney. Tumor volume and serum cre atinine level were analysed 10 days after treatment. In animals pretreated with amifostine there was a delayed adduct formation rate in the normal bra in, and in the kidney cortex the number of tubular cells with extremely hig h adduct level was reduced. No difference in adduct formation was seen in t umors. Tumor volume was significantly larger following amifostine + cisplat in (66% of controls) compared to cisplatin alone (38% of controls). Weight loss was, however, severe in rats given cisplatin alone. In the tumor growt h study only 3 out of 11 rats treated with cisplatin 5 mg/kg alone survived until time of sacrifice at 10 days, whereas all those pretreated with amif ostine survived. Mean serum creatinine was 48 mu mol/l (controls), 146 mu m ol/l (cisplatin) and 59 mu mol/l (amifostine + cisplatin). A marked reducti on of histopathological renal changes was found when amifostine was added. Amifostine thus significantly reduced general and renal toxicity of cisplat in. The tumor growth retardation was stronger when cisplatin was given alon e but this is probably related to general toxicity and malnutrition indirec tly supported by the fact that amifostine did not significantly reduce cisp latin-DNA adduct formation in tumors. The results of the present study sugg est that amifostine may have a role in increasing the therapeutic ratio of cisplatin, also in the treatment of malignant glioma.