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Cited by 38Adrenal and Paraganglionic TumorsAdrenal Hormones and DisordersHormonal Regulation and Hypertension

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

Schteingart, David E., Sinsheimer, Joseph E., Counsell, Raymond E., Abrams, Gerald D., McClellan, Nancy, Djanegara, Tanya, Hines, Jennifer, Ruangwises, Nongluck +2 more·1993·Cancer Chemotherapy and Pharmacology
DOI 10.1007/bf00685036
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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.

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Crossref · 10.1007/bf00685036

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  • In dog adrenal glands, mitotane leads to cell death, most likely via necrosis, followed by emergence of a dense inflammatory infiltrate.

    “In dog adrenal glands, mitotane leads to cell death, most likely via necrosis, and is followed by the emergence of a dense inflammatory infiltrate (283).”

    From Adrenocortical carcinoma (2014) · cites this paper as [283]

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Authors
Schteingart, D. E., Sinsheimer, J. E., Counsell, R. E., Abrams, G. D., McClellan, N., Djanegara, T., Hines, J., Ruangwises, N., Benitez, R., & Wotring, L. L.
Affiliations
University of Michigan (US)
ORCID
Venue
Cancer Chemotherapy and Pharmacology
Publisher
Springer Science and Business Media LLC
Published
1993
Volume
31
Issue
6
Pages
459-466
ISSN
  • 0344-5704 (ISSN-L)
  • 1432-0843
DOI
10.1007/bf00685036
OpenAlex
W2103492084
Cited by
38
References
27
Citations by year
2025: 1 · 2018: 2 · 2017: 1 · 2015: 1 · 2014: 2 · 2013: 3 · 2012: 4
FWCI
1.81
Type
journal article
Language
en
Open access
closed
Licence
www.springer.com/tdm (tdm)
Locations
  • Cancer Chemotherapy and Pharmacology (publishedVersion)
  • PubMed (publishedVersion)
  • Deep Blue (University of Michigan) (acceptedVersion)
Funders
  • National Institutes of Health (5r01ca037794-06)
  • National Cancer Institute (2P30CA-46592, R01 CA 37794, P30CA046592)
Topics
  • Health Sciences › Medicine › Surgery › Adrenal and Paraganglionic Tumors
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal Regulation and Hypertension
Keywords
mitotane, adrenocortical carcinoma, cortisol suppression, ACTH, adrenal cortex, drug toxicity, liver necrosis, adrenal hemorrhage, NCI-H295 cells, drug metabolism, bioavailability
MeSH terms
Adrenal Cortex, Adrenal Cortex Neoplasms, Animals, Carcinoma, Cell Division, Dogs, Female, Guinea Pigs, Humans, Hydrocortisone, Mitotane, Structure-Activity Relationship, Tumor Cells, Cultured

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