title: Of mice and men--warning: intact versus castrated adult male mice as xenograft hosts are equivalent to hypogonadal versus abiraterone treated aging human males, respectively.
abstract: BACKGROUND
  Immune deficient male mice bearing human prostate cancer xenografts are used to evaluate therapeutic response to novel androgen ablation approaches and the results compared to surgical castration based upon assumption that testosterone microenvironment in intact and castrated adult male mice mimics eugonadal and castrated aging adult human males.
  
  
  METHODS
  To test these assumptions, serum total testosterone (TT) and free testosterone (FT) were determined longitudinally in groups (n > 20) of intact versus castrated adult male nude, NOG, and immune competent C57BL/6 mice.
  
  
  RESULTS
  In adult male mice, TT and FT varies by 30- to 100-fold within the same animal providing a microenvironment that is only equivalent to hypogonadal, not eugonadal, adult human males (TT is 1.7 ± 1.2 ng/ml [5.8 ± 4.1 nM] in nude and 2.5 ± 1.3 ng/ml [8.7 ± 4.4 nM] in NOG mice versus >4.2 ng/ml [14.7 nM] in eugonadal humans). This was confirmed based upon enhanced growth of androgen dependent human prostate cancer xenografts inoculated into mice supplemented with exogenous testosterone to elevate and chronically maintain serum TT at a level (5 ng/ml [18 nM]) equivalent to a 50-year-old eugonadal human male. In castrated mice, TT and FT range from 2 to 20 pg/ml (7-70 pM) and <0.8 pg/ml (<2.6 pM), respectively, which is equivalent to castrate resistant prostate cancer (CRPC) patients treated with abiraterone. This was confirmed based upon the inability of another CYP17A1 inhibitor, ketoconazole, to inhibit the growth of CRPC xenografts in castrated mice.
  
  
  CONCLUSIONS
  Adult male mice supplemented with testosterone mimic eugonadal human males, while unsupplemented animals mimic standard androgen ablation and castrated animals mimic abiraterone treated patients. These studies confirm what is claimed in Robert Burns' poem "To a Mouse" that "The best laid schemes of mice and men/often go awry.".
authors.affiliation: Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, School of Medicine, The Johns Hopkins University, Baltimore, Maryland 21287, USA.
authors.forename: J P
authors.initials: JP
authors.lastname: Michiel Sedelaar
authors.forename: Susan S
authors.initials: SS
authors.lastname: Dalrymple
authors.forename: John T
authors.initials: JT
authors.lastname: Isaacs
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000097:blood* / Q000187:drug effects; D000736:Androstenes; D000737:Androstenols / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D045744:Cell Line, Tumor; D006801:Humans; D007006:Hypogonadism / Q000097:blood* / Q000139:chemically induced; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008875:Middle Aged; D009919:Orchiectomy; D013739:Testosterone / Q000097:blood*; D023041:Xenograft Model Antitumor Assays / Q000379:methods*
chemical_list: D000736:Androstenes; D000737:Androstenols; D013739:Testosterone; C089740:abiraterone
keywords: eugonadal levels; free testosterone; hypogonadal levels; mice versus humans; serum total testosterone