title: A phase 2 cancer chemoprevention biomarker trial of isoflavone G-2535 (genistein) in presurgical bladder cancer patients.
abstract: The soy compound genistein has been observed preclinically to inhibit bladder cancer growth with one potential mechanism being the inhibition of epidermal growth factor receptor phosphorylation (p-EGFR). A phase 2 randomized, placebo-controlled trial investigated whether daily, oral genistein (300 or 600 mg/d as the purified soy extract G-2535) for 14 to 21 days before surgery alters molecular pathways in bladder epithelial tissue in 59 subjects diagnosed with urothelial bladder cancer (median age, 71 years). G-2535 treatment was well tolerated; observed toxicities were primarily mild to moderate gastrointestinal or metabolic and usually not attributed to study drug. Genistein was detected in plasma and urine of subjects receiving G-2535 at concentrations greater than placebo subjects' but were not dose-dependent. Reduction in bladder cancer tissue p-EGFR staining between the placebo arm and the combined genistein arms was significant at the protocol-specified significance level of 0.10 (P = 0.07). This difference was most prominent when comparing the 300-mg group with placebo (P = 0.015), but there was no significant reduction in p-EGFR staining between the 600-mg group and placebo. No difference in normal bladder epithelium p-EGFR staining was observed between treatment groups. No significant differences in tumor tissue staining between treatment groups were observed for COX-2, Ki-67, activated caspase-3, Akt, p-Akt, mitogen-activated protein kinase (MAPK), or p-MAPK. No significant differences in urinary survivin or BLCA-4 levels between treatment groups were observed. Genistein displayed a possible bimodal effect (more effective at the lower dose) on bladder cancer tissue EGFR phosphorylation that should be evaluated further, possibly in combination with other agents.
authors.affiliation: University of Rochester Medical Center, Rochester, New York, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Messing
authors.forename: Jason R
authors.initials: JR
authors.lastname: Gee
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Saltzstein
authors.forename: KyungMann
authors.initials: K
authors.lastname: Kim
authors.forename: Anthony
authors.initials: A
authors.lastname: diSant'Agnese
authors.forename: Jill
authors.initials: J
authors.lastname: Kolesar
authors.forename: Linda
authors.initials: L
authors.lastname: Harris
authors.forename: Adrienne
authors.initials: A
authors.lastname: Faerber
authors.forename: Thomas
authors.initials: T
authors.lastname: Havighurst
authors.forename: Jay M
authors.initials: JM
authors.lastname: Young
authors.forename: Mitchell
authors.initials: M
authors.lastname: Efros
authors.forename: Robert H
authors.initials: RH
authors.lastname: Getzenberg
authors.forename: Marcia A
authors.initials: MA
authors.lastname: Wheeler
authors.forename: Joseph
authors.initials: J
authors.lastname: Tangrea
authors.forename: Howard
authors.initials: H
authors.lastname: Parnes
authors.forename: Margaret
authors.initials: M
authors.lastname: House
authors.forename: J Erik
authors.initials: JE
authors.lastname: Busby
authors.forename: Raymond
authors.initials: R
authors.lastname: Hohl
authors.forename: Howard
authors.initials: H
authors.lastname: Bailey
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D015415:Biomarkers / Q000378:metabolism*; D003131:Combined Modality Therapy; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D019833:Genistein / Q000097:blood / Q000494:pharmacology* / Q000652:urine; D006801:Humans; D007529:Isoflavones / Q000097:blood / Q000737:chemistry* / Q000652:urine; D008297:Male; D008875:Middle Aged; D010919:Placebos; D013025:Glycine max / Q000378:metabolism; D013997:Time Factors; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000601:surgery*
chemical_list: D016588:Anticarcinogenic Agents; D015415:Biomarkers; D007529:Isoflavones; D010919:Placebos; C004742:daidzein; D019833:Genistein; D066246:ErbB Receptors