Structural requirements for mitotane activity: development of analogs for treatment of adrenal cancer.

Abstract

AIM:

Mitotane is used in adrenal cancer as adjuvant therapy, monotherapy or combined with other cytotoxic agents in advanced disease, but only 30% of patients respond. The aim of this study was to define the structural requirements for drug activity and to develop analogs with improved adrenalytic action.

MATERIALS AND METHODS:

Nine analogs of [1-(2-chlorophenyl)-1-(4-chlorophenyl)-2,2dichloroethane] (o,p'-DDD) were tested by measuring suppression of cortisol secretion and the presence of inflammatory changes in the dog adrenal and inhibition of cell proliferation and cortisol production by NCI-H295 human adrenal cancer cells.

RESULTS:

In addition to mitotane, o,p'-DDClBr and o,p'-DDBr(2), were active in vitro and in vitro: Their effects were comparable to that of o,p'-DDD when tested at 50 μM concentration, but o,p'DDBr(2) was significantly more active at the lower 20 μM concentration.

CONCLUSION:

A dihalogenated methine carbon is required for adrenalytic activity. A change in the aromatic portion of the mitotane molecule causes loss of activity. Because of its greater activity at lower concentrations, o,p'-DDBr(2) has potential application in the treatment of patients with adrenal cancer.

• Authors: David E Schteingart, Joseph E Sinsheimer, Ricardo S Benitez, Dominic F Homan, Timothy D Johnson, Raymond E Counsell
• Journal: Anticancer research (Anticancer Res) Vol. 32 Issue 7 Pg. 2711-20 (Jul 2012) ISSN: 1791-7530 [Electronic] Greece
• PMID: 22753730 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antineoplastic Agents, Hormonal
• Mitotane
• Adrenocorticotropic Hormone
• Hydrocortisone

Topics

• Adrenal Gland Neoplasms (drug therapy)
• Adrenal Glands (drug effects, metabolism)
• Adrenocorticotropic Hormone (pharmacology)
• Animals
• Antineoplastic Agents, Hormonal (chemistry, pharmacology)
• Cell Growth Processes (drug effects)
• Cell Line, Tumor
• Dogs
• Dose-Response Relationship, Drug
• Humans
• Hydrocortisone (blood, metabolism)
• Mitotane (analogs & derivatives, chemistry, pharmacology)
• Structure-Activity Relationship