title: Structural requirements for mitotane activity: development of analogs for treatment of adrenal cancer.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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: Department of Internal Medicine, Division of Metabolism, Endocrinology and Diabetes, University of Michigan. Rm 5570, MSRB 2. 1150 West Medical Center Dr, Ann Arbor, MI 48109, USA. dschtein@umich.edu
authors: David E
authors: DE
authors: Schteingart
authors: Joseph E
authors: JE
authors: Sinsheimer
authors: Ricardo S
authors: RS
authors: Benitez
authors: Dominic F
authors: DF
authors: Homan
authors: Timothy D
authors: TD
authors: Johnson
authors: Raymond E
authors: RE
authors: Counsell
mesh_terms: D000310:Adrenal Gland Neoplasms / Q000188:drug therapy*; D000311:Adrenal Glands / Q000187:drug effects / Q000378:metabolism; D000324:Adrenocorticotropic Hormone / Q000494:pharmacology; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000737:chemistry* / Q000494:pharmacology*; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006854:Hydrocortisone / Q000097:blood / Q000378:metabolism; D008939:Mitotane / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D018931:Antineoplastic Agents, Hormonal; D008939:Mitotane; D000324:Adrenocorticotropic Hormone; D006854:Hydrocortisone