Phase I pharmacokinetic and pharmacodynamic analysis of unconjugated soy isoflavones administered to individuals with cancer.
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.
Takimoto
Chris H
CH
Department of Medicine, Northwestern University Medical School and the Robert H Lurie Cancer Center of Northwestern University, Chicago, Illinois, USA.
Glover
Kira
K
Huang
Xiaoke
X
Hayes
Steven A
SA
Gallot
Lilia
L
Quinn
Mary
M
Jovanovic
Borko D
BD
Shapiro
Alla
A
Hernandez
Leticia
L
Goetz
Andrew
A
Llorens
Victor
V
Lieberman
Ronald
R
Crowell
James A
JA
Poisson
Brett A
BA
Bergan
Raymond C
RC
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
D000970:Antineoplastic Agents; D007529:Isoflavones; D014443:Tyrosine; D019833:Genistein