# DEVELOPMENT OF MITOTANE ANALOGS FOR ADRENAL CANCER

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 1989 · $183,355

## Abstract

Mitotane (o,p'-DDD) is an adrenalytic drug used in the treatment of
adrenal cancer and benign Cushing's syndrome.  When given in effective
doses, its use is limited by toxicity.  The aim of this investigation is
to develop more effective protocols for the administration of Mitotane
and Mitotane analogs which should yield greater adrenalytic effects and
decreased toxicity.  Based on our previous studies with Mitotane and
Mitometh and reports on the activation metabolism of p,p'-DDD and other
halogenated hydrocarbons, we postulate that the adrenalytic action of
Mitotane is linked to the ability of the dichloromethyl group to become
metabolically oxidized to an activated electrophylic species, an acyl
chloride, which covalently binds to metabolically important
macromolecules in the adrenal cortex.  We plan to study this mechanism
further using a dog model in which the adrenalytic effect will be
assessed by suppression of cortisol and increase in ACTH levels, adrenal
response to ACTH stimulation, histological evidence of adrenal necrosis
and in vitro suppression of transformation of radiolabeled Mitotane to
DDA.  We will determine if the administration of cytochrome P-450 enzyme
mitochondrial inhibitors can block Mitotane effects by suppressing its
metabolism and if the administration of P-450 inducers can enhance the
adrenalytic effects of the drug.  We will determine by autoradiographic
morphological studies the cellular site(s) of Mitotane metabolism and
action.  In order to increase activity of Mitotane, we plan to synthesize
bromochloro and bromofluoro analogs.  These substitutions may render
compounds which are more cytotoxic to the adrenal.

Another goal of the study is to ascertain ways in which toxicity of
Mitotane may be ameliorated.  Toxicity will be evaluated in the dog by
assessing changes in serum cholesterol, SGOT, SGPT, alkaline phosphatase
and histological evidence of hepatic necrosis.  We plan to determine if
there are differences in metabolic pathways in adrenal as compared to
liver in regards to the effects of Mitotane and its analogs and to
investigate the role of glutathione in the bioactivation or
detoxification of Mitotane metabolites.  Assuming that the toxicity of
Mitotane may be due, in part, to its high lipophilicity and poor
absorption, we plan to synthesize Mitotane analogs in which one or both
of the aromatic chlorines is replaced with amino groups.  By these
changes, we may obtain a better balance between lipophilicity and
hydrophilicity in order to improve absorption and adrenal
bioavailability.

If enzyme inducers are able to enhance the activity of Mitotane in the
adrenal without added toxicity and if the new Mitotane analogs appear to
have a more favorable therapeutic index, we plan to carry out a pilot
study in which these compounds will be used in dogs with Cushing's
disease and adrenal cancer.  We also plan to determine if it is possible
to predict the response to therapy by measuring metabolic activity in
vitro...

## Key facts

- **NIH application ID:** 3175624
- **Project number:** 2R01CA037794-04A1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **SAM.gov UEI:** GNJ7BBP73WE9
- **Principal Investigator:** DAVID Eduardo SCHTEINGART
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1989
- **Award amount:** $183,355
- **Award type:** 2
- **Project period:** 1984-08-01 → 1992-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3175624

## Citation

> US National Institutes of Health, RePORTER application 3175624, DEVELOPMENT OF MITOTANE ANALOGS FOR ADRENAL CANCER (2R01CA037794-04A1). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/3175624. Licensed CC0.

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