title: Phase I pharmacokinetic and pharmacodynamic analysis of unconjugated soy isoflavones administered to individuals with cancer.
abstract: Preclinical studies suggest that the isoflavone genistein may have prostate cancer chemopreventive activity. Genistein has been shown to alter cellular levels of protein-tyrosine phosphorylation and is present at high levels in soy. This study was designed to measure the pharmacokinetic parameters of two different preparations of unconjugated soy isoflavones, PTI G-2535 and PTI G-4660 (which contain 43% and 90% genistein, respectively), in human subjects with cancer, to evaluate toxicity and obtain pilot data on in vivo effects on protein-tyrosine phosphorylation. Cohorts of four patients were given single doses of each preparation; each dose was separated by 1 week. Sequential cohorts received genistein at 2, 4, or 8 mg/kg orally. Pharmacokinetic sampling was performed after each dose, and tyrosine phosphorylation was measured in proteins extracted from peripheral blood mononuclear cells. One of 13 patients treated developed a treatment-related rash. No other toxicities were observed. Maximal plasma concentrations (C(max)) ranged between 4.3 and 16.3 micro M for total genistein and 0.066 and 0.17 micro M for free genistein. For PTI G-2535 and PTI G-4660, half-life was 15.03 and 22.41 h, respectively, and volume of distribution was 189.9 and 653.8 liters, respectively, and there was a trend toward higher area under the concentration curve for PTI G-2535 (P = 0.07 at the 8 mg/kg dose). Treatment-related increases in tyrosine phosphorylation were observed in peripheral blood mononuclear cells. Oral administration of soy isoflavones gives plasma concentrations of genistein that have been associated with antimetastatic activity in vitro.
authors.affiliation: Department of Medicine, Northwestern University Medical School and the Robert H Lurie Cancer Center of Northwestern University, Chicago, Illinois, USA.
authors.forename: Chris H
authors.initials: CH
authors.lastname: Takimoto
authors.forename: Kira
authors.initials: K
authors.lastname: Glover
authors.forename: Xiaoke
authors.initials: X
authors.lastname: Huang
authors.forename: Steven A
authors.initials: SA
authors.lastname: Hayes
authors.forename: Lilia
authors.initials: L
authors.lastname: Gallot
authors.forename: Mary
authors.initials: M
authors.lastname: Quinn
authors.forename: Borko D
authors.initials: BD
authors.lastname: Jovanovic
authors.forename: Alla
authors.initials: A
authors.lastname: Shapiro
authors.forename: Leticia
authors.initials: L
authors.lastname: Hernandez
authors.forename: Andrew
authors.initials: A
authors.lastname: Goetz
authors.forename: Victor
authors.initials: V
authors.lastname: Llorens
authors.forename: Ronald
authors.initials: R
authors.lastname: Lieberman
authors.forename: James A
authors.initials: JA
authors.lastname: Crowell
authors.forename: Brett A
authors.initials: BA
authors.lastname: Poisson
authors.forename: Raymond C
authors.initials: RC
authors.lastname: Bergan
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D005260:Female; D019833:Genistein / Q000493:pharmacokinetics* / Q000494:pharmacology*; D006801:Humans; D007529:Isoflavones / Q000493:pharmacokinetics* / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D010766:Phosphorylation; D013025:Glycine max / Q000737:chemistry; D014443:Tyrosine / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D007529:Isoflavones; D014443:Tyrosine; D019833:Genistein