We have previously shown that toxicity of the anticancer agent hydroxyurea (HU) in the rat is markedly increased by hypophysectomy or adrenalectomy. In this study, we investigated whether increased toxicity in ablated animals is a unique feature of HU or it is shared with other anticancer agents; the toxic effects of five such drugs have been compared in intact, hypophysectomized (HYX) and adrenalectomized (ADX) rats. Bis-chloroethyl-nitrosourea (BCNU, 5-10 mg/kg), busulfan (0.1-10 mg/kg), cyclophosphamide (25-125 mg/kg), 5-fluorouracil (15-75 mg/kg) and vindesine (0.1-0.5 mg/kg) were given to intact and endocrine-ablated rats, and lethality was recorded over 3 weeks. It was found that mortality was low or absent in intact rats, whereas (with the exception of HYX rats receiving the highest dose of busulfan) it was dramatically increased by both hypophysectomy and adrenalectomy. However, replacement treatments with long-acting tetracosactrin and corticosterone to HYX and ADX rats respectively afforded significant protection against BCNU toxicity only. We conclude that the integrity of the hypothalamo-pituitary-adrenal axis is needed to tolerate the toxicity of various anticancer drugs, although complex mechanisms appear to underlie such protective effect.