Replacement therapy against increased hydroxyurea toxicity in pituitary or adrenal ablated rats.

Abstract

The main rat adrenocortical hormone, corticosterone, the mineralocorticoid, 11-deoxycorticosterone (DCA) acetate given alone or together (2:1 ratio) twice daily at doses of 2-4 and 1-8 mg/kg, DCA enanthate given in a single injection of 20 mg/kg 0-3 days before the beginning of the experiments and a highly-concentrated injectable extract of the adrenal cortex (4 mg/kg as hydrocortisone twice a day) given by the intramuscular route, delay and partially protect against the increased toxicity following administration of the anticancer drug, hydroxyurea (800 mg/kg/day for 5 days) in adrenalectomized or hypophysectomized animals (80-100% lethality; in control non ablated rats 0-10% lethality). ACTH1-24 (tetracosactide) also proved effective in pituitary ablated rats. The best protection was afforded with the joint administration of corticosterone and DCA (2-4 and 1-2 mg/kg twice a day) or with corticosterone alone at doses (4 mg/kg twice a day) capable of giving plasma levels, six hours after administration on the third day, similar to those observed in non ablated rats receiving HYD in the morning. The adrenocortical hormones may replace a possible unique defense mechanism against drug toxicity, which is lacking in pituitary or adrenal ablated rats.