title: Phase I and clinical pharmacology of a type I and II, 5-alpha-reductase inhibitor (LY320236) in prostate cancer: elevation of estradiol as possible mechanism of action.
abstract: OBJECTIVE
  To study the safety, pharmacokinetics, biologic activity, and preliminary efficacy of the bispecific 5-alpha-reductase inhibitor (LY320236) in prostate cancer.
  
  
  METHODS
  Fifty-one patients with recurrent or metastatic prostate cancer were sequentially (nonrandomly) assigned in cohorts to receive one of five single daily oral doses of LY320236 (10, 50, 150, 250, and 500 mg). Serial evaluations included serum testosterone, dihydrotestosterone, androstenediol glucuronide, estradiol, and pharmacokinetics on days 1, 29, and 57. Toxicity assessments, x-rays/scans, and blood tests, including serum prostate-specific antigen (PSA) determination, were done at regular intervals.
  
  
  RESULTS
  Overall, treatment was well tolerated, with 3 of 51 patients developing reversible grade 3-4 toxicity (one diarrhea, two elevated liver enzymes). Peak blood levels (2 to 3 hours after drug administration) were greater for doses of 150 mg or greater compared with less than 150-mg doses with slow accumulation. Serum levels of testosterone, dihydrotestosterone, and androstenediol glucuronide did not change significantly during treatment; however, a statistically significant increase occurred in serum estradiol levels in both the castration and noncastration groups. One of 26 in the noncastration group and 4 (27%) of 15 in the castration group with baseline PSA levels of 5 ng/mL or greater had a 50% or greater PSA decline for 4 weeks or longer.
  
  
  CONCLUSIONS
  LY320236 treatment is associated with modest reversible toxicity. An elevation of estradiol levels was seen in both castration and noncastration groups, although PSA declines were primarily seen in the castration group. The absence of cardiovascular toxicity suggests that this agent may be a promising alternative to exogenous estrogens in patients with prostate cancer who demonstrate evidence of disease progression after initial androgen deprivation treatment.
authors.affiliation: Johns Hopkins Medical Institutions, Baltimore, Maryland 21231-1000, USA.
authors.forename: Mario A
authors.initials: MA
authors.lastname: Eisenberger
authors.forename: Menachem
authors.initials: M
authors.lastname: Laufer
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Vogelzang
authors.forename: Oliver
authors.initials: O
authors.lastname: Sartor
authors.forename: Donald
authors.initials: D
authors.lastname: Thornton
authors.forename: Blake Lee
authors.initials: BL
authors.lastname: Neubauer
authors.forename: Victoria
authors.initials: V
authors.lastname: Sinibaldi
authors.forename: Gary
authors.initials: G
authors.lastname: Lieskovsky
authors.forename: Michael A
authors.initials: MA
authors.lastname: Carducci
authors.forename: Mariana
authors.initials: M
authors.lastname: Zahurak
authors.forename: Derek
authors.initials: D
authors.lastname: Raghavan
mesh_terms: D058891:5-alpha Reductase Inhibitors; D000230:Adenocarcinoma / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology / Q000601:surgery; D000726:Androgen Antagonists / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D000734:Androstenediols / Q000097:blood; D016227:Benzoquinones / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology; D013196:Dihydrotestosterone / Q000097:blood; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D004958:Estradiol / Q000097:blood*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D015993:Life Tables; D008297:Male; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000097:blood; D009919:Orchiectomy; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology / Q000601:surgery; D012449:Safety; D013379:Substrate Specificity; D013739:Testosterone / Q000097:blood; D016896:Treatment Outcome
chemical_list: D058891:5-alpha Reductase Inhibitors; D000726:Androgen Antagonists; D000734:Androstenediols; D016227:Benzoquinones; D014408:Biomarkers, Tumor; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D009363:Neoplasm Proteins; D013196:Dihydrotestosterone; D013739:Testosterone; D004958:Estradiol; C407322:Izonsteride; D017430:Prostate-Specific Antigen