Association of the CYP1B1*3 allele with survival in patients with prostate cancer receiving docetaxel

Tristan M. Sissung, Romano Danesi, Douglas K. Price, Seth M. Steinberg, Ronald De Wit, Muhammad Zahid, Nilesh Gaikwad, Ercole Cavalieri, William L. Dahut, Dan L. Sackett, William D. Figg, Alex Sparreboom

Research output: Contribution to journalArticle

62 Citations (Scopus)

Abstract

Using a single nucleotide polymorphism association study in 52 men with prostate cancer receiving docetaxel, we found that individuals carrying two copies of the CYP1B1*3 polymorphic variant had a poor prognosis after docetaxel-based therapies compared with individuals carrying at least one copy of the CYP1B1*1 allele (30.6 versus 12.8 months; P = 0.0004). The association between CYP1B1*3 and response to therapy was not observed in similar subjects receiving non-taxane-based therapy (P = 0.18). The systemic clearance of docetaxel was also unrelated to CYP1B1 genotype status (P = 0.39), indicating that the association of CYP1B1*3 with clinical response is not due to docetaxel metabolism. To explain these results, we hypothesized that an indirect gene-drug interaction was interfering with the primary mechanism of action of docetaxel, tubulin polymerization. We therefore conducted tubulin polymerization experiments with taxanes in the presence or absence of certain CYP1B1 estrogen metabolites, which are known to bind to nucleophilic sites in proteins and DNA, that revealed the primary estrogen metabolite of CYP1B1, 4-hydroxyestradiol (4-OHE2), when oxidized to estradiol-3,4-quinone strongly inhibits tubulin polymerization. The 4-OHE2 is also formed more readily by the protein encoded by the CYP1B1*3 allele, validating further our data in patients. Furthermore, estradiol-3,4-quinone reacted in vitro with docetaxel to form the 4-OHE2-docetaxel adduct. This pilot study provides evidence that CYP1B1*3 may be an important marker for estimating docetaxel efficacy in patients with prostate cancer. This link is likely associated with CYP1B1*3 genotype-dependent estrogen metabolism.

Original languageEnglish (US)
Pages (from-to)19-26
Number of pages8
JournalMolecular cancer therapeutics
Volume7
Issue number1
DOIs
StatePublished - Jan 1 2008

Fingerprint

docetaxel
Prostatic Neoplasms
Alleles
Survival
Tubulin
Polymerization
Estrogens
Genotype
Taxoids
Drug Interactions
Single Nucleotide Polymorphism

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Association of the CYP1B1*3 allele with survival in patients with prostate cancer receiving docetaxel. / Sissung, Tristan M.; Danesi, Romano; Price, Douglas K.; Steinberg, Seth M.; De Wit, Ronald; Zahid, Muhammad; Gaikwad, Nilesh; Cavalieri, Ercole; Dahut, William L.; Sackett, Dan L.; Figg, William D.; Sparreboom, Alex.

In: Molecular cancer therapeutics, Vol. 7, No. 1, 01.01.2008, p. 19-26.

Research output: Contribution to journalArticle

Sissung, TM, Danesi, R, Price, DK, Steinberg, SM, De Wit, R, Zahid, M, Gaikwad, N, Cavalieri, E, Dahut, WL, Sackett, DL, Figg, WD & Sparreboom, A 2008, 'Association of the CYP1B1*3 allele with survival in patients with prostate cancer receiving docetaxel', Molecular cancer therapeutics, vol. 7, no. 1, pp. 19-26. https://doi.org/10.1158/1535-7163.MCT-07-0557
Sissung, Tristan M. ; Danesi, Romano ; Price, Douglas K. ; Steinberg, Seth M. ; De Wit, Ronald ; Zahid, Muhammad ; Gaikwad, Nilesh ; Cavalieri, Ercole ; Dahut, William L. ; Sackett, Dan L. ; Figg, William D. ; Sparreboom, Alex. / Association of the CYP1B1*3 allele with survival in patients with prostate cancer receiving docetaxel. In: Molecular cancer therapeutics. 2008 ; Vol. 7, No. 1. pp. 19-26.
@article{9d51312bb2b3414792ce79f16635664d,
title = "Association of the CYP1B1*3 allele with survival in patients with prostate cancer receiving docetaxel",
abstract = "Using a single nucleotide polymorphism association study in 52 men with prostate cancer receiving docetaxel, we found that individuals carrying two copies of the CYP1B1*3 polymorphic variant had a poor prognosis after docetaxel-based therapies compared with individuals carrying at least one copy of the CYP1B1*1 allele (30.6 versus 12.8 months; P = 0.0004). The association between CYP1B1*3 and response to therapy was not observed in similar subjects receiving non-taxane-based therapy (P = 0.18). The systemic clearance of docetaxel was also unrelated to CYP1B1 genotype status (P = 0.39), indicating that the association of CYP1B1*3 with clinical response is not due to docetaxel metabolism. To explain these results, we hypothesized that an indirect gene-drug interaction was interfering with the primary mechanism of action of docetaxel, tubulin polymerization. We therefore conducted tubulin polymerization experiments with taxanes in the presence or absence of certain CYP1B1 estrogen metabolites, which are known to bind to nucleophilic sites in proteins and DNA, that revealed the primary estrogen metabolite of CYP1B1, 4-hydroxyestradiol (4-OHE2), when oxidized to estradiol-3,4-quinone strongly inhibits tubulin polymerization. The 4-OHE2 is also formed more readily by the protein encoded by the CYP1B1*3 allele, validating further our data in patients. Furthermore, estradiol-3,4-quinone reacted in vitro with docetaxel to form the 4-OHE2-docetaxel adduct. This pilot study provides evidence that CYP1B1*3 may be an important marker for estimating docetaxel efficacy in patients with prostate cancer. This link is likely associated with CYP1B1*3 genotype-dependent estrogen metabolism.",
author = "Sissung, {Tristan M.} and Romano Danesi and Price, {Douglas K.} and Steinberg, {Seth M.} and {De Wit}, Ronald and Muhammad Zahid and Nilesh Gaikwad and Ercole Cavalieri and Dahut, {William L.} and Sackett, {Dan L.} and Figg, {William D.} and Alex Sparreboom",
year = "2008",
month = "1",
day = "1",
doi = "10.1158/1535-7163.MCT-07-0557",
language = "English (US)",
volume = "7",
pages = "19--26",
journal = "Molecular Cancer Therapeutics",
issn = "1535-7163",
publisher = "American Association for Cancer Research Inc.",
number = "1",

}

TY - JOUR

T1 - Association of the CYP1B1*3 allele with survival in patients with prostate cancer receiving docetaxel

AU - Sissung, Tristan M.

AU - Danesi, Romano

AU - Price, Douglas K.

AU - Steinberg, Seth M.

AU - De Wit, Ronald

AU - Zahid, Muhammad

AU - Gaikwad, Nilesh

AU - Cavalieri, Ercole

AU - Dahut, William L.

AU - Sackett, Dan L.

AU - Figg, William D.

AU - Sparreboom, Alex

PY - 2008/1/1

Y1 - 2008/1/1

N2 - Using a single nucleotide polymorphism association study in 52 men with prostate cancer receiving docetaxel, we found that individuals carrying two copies of the CYP1B1*3 polymorphic variant had a poor prognosis after docetaxel-based therapies compared with individuals carrying at least one copy of the CYP1B1*1 allele (30.6 versus 12.8 months; P = 0.0004). The association between CYP1B1*3 and response to therapy was not observed in similar subjects receiving non-taxane-based therapy (P = 0.18). The systemic clearance of docetaxel was also unrelated to CYP1B1 genotype status (P = 0.39), indicating that the association of CYP1B1*3 with clinical response is not due to docetaxel metabolism. To explain these results, we hypothesized that an indirect gene-drug interaction was interfering with the primary mechanism of action of docetaxel, tubulin polymerization. We therefore conducted tubulin polymerization experiments with taxanes in the presence or absence of certain CYP1B1 estrogen metabolites, which are known to bind to nucleophilic sites in proteins and DNA, that revealed the primary estrogen metabolite of CYP1B1, 4-hydroxyestradiol (4-OHE2), when oxidized to estradiol-3,4-quinone strongly inhibits tubulin polymerization. The 4-OHE2 is also formed more readily by the protein encoded by the CYP1B1*3 allele, validating further our data in patients. Furthermore, estradiol-3,4-quinone reacted in vitro with docetaxel to form the 4-OHE2-docetaxel adduct. This pilot study provides evidence that CYP1B1*3 may be an important marker for estimating docetaxel efficacy in patients with prostate cancer. This link is likely associated with CYP1B1*3 genotype-dependent estrogen metabolism.

AB - Using a single nucleotide polymorphism association study in 52 men with prostate cancer receiving docetaxel, we found that individuals carrying two copies of the CYP1B1*3 polymorphic variant had a poor prognosis after docetaxel-based therapies compared with individuals carrying at least one copy of the CYP1B1*1 allele (30.6 versus 12.8 months; P = 0.0004). The association between CYP1B1*3 and response to therapy was not observed in similar subjects receiving non-taxane-based therapy (P = 0.18). The systemic clearance of docetaxel was also unrelated to CYP1B1 genotype status (P = 0.39), indicating that the association of CYP1B1*3 with clinical response is not due to docetaxel metabolism. To explain these results, we hypothesized that an indirect gene-drug interaction was interfering with the primary mechanism of action of docetaxel, tubulin polymerization. We therefore conducted tubulin polymerization experiments with taxanes in the presence or absence of certain CYP1B1 estrogen metabolites, which are known to bind to nucleophilic sites in proteins and DNA, that revealed the primary estrogen metabolite of CYP1B1, 4-hydroxyestradiol (4-OHE2), when oxidized to estradiol-3,4-quinone strongly inhibits tubulin polymerization. The 4-OHE2 is also formed more readily by the protein encoded by the CYP1B1*3 allele, validating further our data in patients. Furthermore, estradiol-3,4-quinone reacted in vitro with docetaxel to form the 4-OHE2-docetaxel adduct. This pilot study provides evidence that CYP1B1*3 may be an important marker for estimating docetaxel efficacy in patients with prostate cancer. This link is likely associated with CYP1B1*3 genotype-dependent estrogen metabolism.

UR - http://www.scopus.com/inward/record.url?scp=38349148686&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=38349148686&partnerID=8YFLogxK

U2 - 10.1158/1535-7163.MCT-07-0557

DO - 10.1158/1535-7163.MCT-07-0557

M3 - Article

VL - 7

SP - 19

EP - 26

JO - Molecular Cancer Therapeutics

JF - Molecular Cancer Therapeutics

SN - 1535-7163

IS - 1

ER -