Comparison of the adrenalytic activity of mitotane and a methylated homolog on normal adrenal cortex and adrenal cortical carcinoma

Abstract

Mitotane is an important adrenalytic drug for the treatment of adrenal cancer whose use is limited by toxicity. Reports from another laboratory indicated that a methylated homolog of Mitotane (Mitometh) tested in guinea pigs possessed comparable adrenalytic activity but was less toxic than Mitotane. This observation prompted us to undertake a comparative study of these two drugs on the basis that Mitometh may be a superior agent for the treatment of adrenal cancer. Preliminary studies in guinea pigs failed to show a significant adrenalytic effect for either Mitotane or Mitometh. Thus, we extended the study to 13 mongrel dogs weighing 12-15 kg that were treated daily with Mitometh or Mitotane (50-100 mg/kg) for 6 or 12 days. Cortisol decreased to undetectable levels and adrenocorticotropic hormone (ACTH) rose to 10 times the baseline levels within 72 h in Mitotane-treated animals. Despite the achievement of similar drug levels, Mitometh treatment in dogs failed to suppress cortisol or increase ACTH. To determine whether these differences were due to differences in bioavailability, we measured the relative concentration of Mitotane and Mitometh in homogenates of adrenal cortex obtained from Mitotane- and Mitometh-treated dogs. The adrenal concentration of Mitometh determined in Mitometh-treated dogs was 5 times higher than the concentration of Mitotane measured in Mitotane-treated animals. Whereas the adrenal glands of Mitotane-treated dogs showed hemorrhage and necrosis, the Mitometh-treated animals showed no adrenal damage. Despite the lack of adrenalytic activity, Mitometh maintained its toxicity as demonstrated by microscopic evidence of hepatic necrosis and an increase in hepatic enzymes. The adrenalytic effects of both agents was also studied in vitro using a human functioning adrenal cortical carcinoma cell line, NCI-H295. Whereas Mitotane strongly suppressed cell growth, Mitometh had a weaker effect. We conclude that Mitometh is not likely to be effective in the therapy of adrenal cancer. Moreover, the results of this study are supportive of the view that metabolic transformation of Mitotane is in some way linked to its adrenalytic action.

Mitotane alters mitochondrial respiratory chain activity by inducing cytochrome c oxidase defect in human adrenocortical cells

“…It has been suggested that the metabolic transformation of o,p'-DDD is carried out in the adrenal mitochondria, the first enzymatic step being catalyzed by an unknown P450 cytochrome-mediated hydroxylase leading to an adrenolytic effect (Martz & Straw 1977, Cai et al 1995. In accordance with previous studies, we confirmed that mitotane inhibits steroidogenesis reducing cortisol and 17-OH-progesterone secretions by 70% (Schteingart et al 1993, Stigliano et al 2008. Mitotane exposure also decreased mRNA levels of STAR, the cholesterol carrier into the mitochondria, as well as CYP11A, CYP11B1, and CYP11B2, three mt enzymes involved in cortisol and aldosterone biosynthesis respectively.…”

Modulation of proteomic profile in H295R adrenocortical cell line induced by mitotane

“…Cell proliferation and treatment Schteingart et al (1993) reported that mitotane at 10 K5 M concentration inhibits cortisol secretion in H295R cell line, with minimal effects on cell viability. Therefore, we have used this dose to evaluate the mitotane effect on cell growth and cell cycle at different times on these cells.…”

“…Mitotane acts selectively on the adrenal cortex leading to cell destruction and the impairment of steroidogenesis (Fang 1979, Martz & Straw 1980. At higher concentrations, mitotane produces a dose-related cellular toxic effect with damage on the fasciculata/reticularis areas causing rupture of mitochondrial membranes, but with a minimal effect in the glomerulosa area (Schteingart et al 1993). It is usually well tolerated in the plasmatic narrow range between 14 and 20 mg/l.…”

THERAPY OF ENDOCRINE DISEASE: Steroidogenesis enzyme inhibitors in Cushing's syndrome

“…It causes a reduction in cortisol and adrenal androgens levels, but the aldosterone production is not significantly affected with short-term treatment (67,68). The metabolites of mitotane have a direct toxic effect on the mitochondria of the adrenal cells causing cellular necrosis (69,70,71,72). Macroscopically, this mainly affects the zona reticularis and zona fascicularis, leaving the zona glomerulosa relatively spared (73,74).…”