Hydroxyurea: relationship between toxicity and centrally-induced adrenal activation.

Area of Science:

• Pharmacology
• Endocrinology
• Toxicology

Background:

• Hydroxyurea (HU) is an anticancer drug with known toxicities.
• The role of the hypothalamic-hypophyseal-adrenal (HPA) axis in mediating HU toxicity is not fully understood.
• Previous studies suggest potential endocrine involvement in drug responses.

Purpose of the Study:

• To investigate the role of the HPA axis in hydroxyurea-induced lethality.
• To determine if adrenal function protects against HU toxicity.
• To elucidate the mechanisms underlying HU's effects on the HPA axis.

Main Methods:

• Rats underwent hypophysectomy or adrenalectomy and received HU at varying doses.
• Control groups received saline + 5% glucose.
• Adrenal stimulatory or replacement therapies were administered to ablated rats.
• Plasma corticosterone and epinephrine levels were measured.
• White blood cell counts were analyzed.

Main Results:

• Hydroxyurea caused dramatic lethality (up to 100%) in hypophysectomized and adrenalectomized rats.
• Adrenal stimulatory or replacement therapies significantly protected against HU toxicity and lethality.
• HU induced a dose-dependent increase in plasma corticosterone in normal rats, but not in hypophysectomized rats.
• HU treatment led to increased plasma epinephrine, secondary to corticosterone elevation.
• The HPA axis stimulation by HU was identified as a protective mechanism.

Conclusions:

• The hypothalamic-hypophyseal-adrenal axis activation is a critical defense mechanism against hydroxyurea toxicity.
• Failure of this axis, due to pituitary or adrenal ablation, leads to severe hydroxyurea-induced lethality.
• Adrenal function is essential for protecting rats against the toxic effects of hydroxyurea.