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.