| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Section of Molecular Carcinogenesis, The Institute of Cancer Research, Haddow Laboratories, Sutton, Surrey SM2 5NG, United Kingdom [P. L. C., A. J. H., G. K. P., D. H. P.]; Department of Obstetrics and Gynaecology, St. Helier Hospital, Wrythe Lane, Carshalton, Surrey SM5 1AA, United Kingdom [A. H. N. U.]; and Algemene Kliniek St. Jan, Broekstraat 114, 1000 Brussels, Belgium [P. N.]
The potential for the anti-breast cancer drug tamoxifen [(Z)-1-[4-[2-(dimethylamino)ethoxy]phenyl]-1,2-diphenyl-1-butene] to induce genotoxic damage (DNA adducts) in the human endometrium was investigated in vivo and in vitro. Endometria from hysterectomy patients who were not on tamoxifen were sectioned and maintained in short-term organ culture. The cultures were treated with either solvent vehicle (DMSO), tamoxifen, 
-hydroxytamoxifen [(E)-1-[4-[2-(dimethylamino)ethoxy]phenyl]-1,2-diphenyl-1-buten-3-ol; the major DNA-reactive metabolite in the rat], or benzo(a)pyrene. DNA was isolated and analyzed by 32P postlabeling. Chromatography on polyethyleneimine-cellulose TLC plates revealed DNA adducts in endometria treated with -hydroxytamoxifen identical to those seen previously in the rat liver. However, no adducts were seen from treatment with tamoxifen itself. The viability of the enzyme-metabolizing systems of the endometrial samples was demonstrated by the detection of expected DNA adducts induced by benzo(a)pyrene. Examination by liquid chromatography-mass spectrometry of the explant culture media from endometria treated with tamoxifen revealed the presence of the -hydroxy metabolite in a dose-dependent manner, although apparently at levels insufficient to produce detectable DNA adducts. Endometrial DNA obtained from 18 patients undergoing daily treatment with 10–40 mg tamoxifen for 3 months-9 years was also analyzed. No evidence for any DNA adducts induced by tamoxifen was found in any of the patients examined. These data suggest that the genotoxic events observed with tamoxifen in the rat may not apply to the human endometrium.
1 This work was supported by the Cancer Research Campaign.
2 To whom requests for reprints should be addressed.
Received 1/12/96. Accepted 2/23/96.
This article has been cited by other articles:
|
|
 |
|
  W. Chu, A. Fyles, E. M. Sellers, D. R. McCready, J. Murphy, T. Pal, and S. A. Narod Association between CYP3A4 genotype and risk of endometrial cancer following tamoxifen use Carcinogenesis, October 1, 2007; 28(10): 2139 - 2142. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Brown, E. M. Tompkins, D. J. Boocock, E. A. Martin, P. B. Farmer, K. W. Turteltaub, E. Ubick, D. Hemingway, E. Horner-Glister, and I. N.H. White Tamoxifen Forms DNA Adducts in Human Colon after Administration of a Single [14C]-Labeled Therapeutic Dose Cancer Res., July 15, 2007; 67(14): 6995 - 7002. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Y. Kim, N. Suzuki, Y. R. S. Laxmi, and S. Shibutani INEFFICIENT REPAIR OF TAMOXIFEN-DNA ADDUCTS IN RATS AND MICE Drug Metab. Dispos., February 1, 2006; 34(2): 311 - 317. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Osipo, K. Meeke, H. Liu, D. Cheng, S. Lim, A. Weichel, and V. C. Jordan Trastuzumab Therapy for Tamoxifen-Stimulated Endometrial Cancer Cancer Res., September 15, 2005; 65(18): 8504 - 8513. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. H. Phillips, A. Hewer, M. R. Osborne, K. J. Cole, C. Churchill, and V. M. Arlt Organ specificity of DNA adduct formation by tamoxifen and {alpha}-hydroxytamoxifen in the rat: implications for understanding the mechanism(s) of tamoxifen carcinogenicity and for human risk assessment Mutagenesis, July 1, 2005; 20(4): 297 - 303. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. J. Schild, D. H. Phillips, M. R. Osborne, A. Hewer, F. A. Beland, M. I. Churchwell, K. Brown, M. Gaskell, E. Wright, and M. C. Poirier Hepatic DNA adduct dosimetry in rats fed tamoxifen: a comparison of methods Mutagenesis, March 1, 2005; 20(2): 115 - 124. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. I. Apak and M. W. Duffel INTERACTIONS OF THE STEREOISOMERS OF {alpha}-HYDROXYTAMOXIFEN WITH HUMAN HYDROXYSTEROID SULFOTRANSFERASE SULT2A1 AND RAT HYDROXYSTEROID SULFOTRANSFERASE STA Drug Metab. Dispos., December 1, 2004; 32(12): 1501 - 1508. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. L. Martin and K. T. Semple Environmental health impacts: occurrence, exposure and significance, Lancaster University, UK, 9-10 September 2003 Mutagenesis, September 1, 2004; 19(5): 423 - 429. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. A. Beland, M. I. Churchwell, D. R. Doerge, D. R. Parkin, D. Malejka-Giganti, A. Hewer, D. H. Phillips, P. L. Carmichael, G. Gamboa da Costa, and M. M. Marques Electrospray Ionization-Tandem Mass Spectrometry and 32P-Postlabeling Analyses of Tamoxifen-DNA Adducts in Humans J Natl Cancer Inst, July 21, 2004; 96(14): 1099 - 1104. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. A. Martin, K. Brown, M. Gaskell, F. Al-Azzawi, R. C. Garner, D. J. Boocock, E. Mattock, D. W. Pring, K. Dingley, K. W. Turteltaub, et al. Tamoxifen DNA Damage Detected in Human Endometrium Using Accelerator Mass Spectrometry Cancer Res., December 1, 2003; 63(23): 8461 - 8465. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. J. Schild, R. L. Divi, F. A. Beland, M. I. Churchwell, D. R. Doerge, G. Gamboa da Costa, M. M. Marques, and M. C. Poirier Formation of Tamoxifen-DNA Adducts in Multiple Organs of Adult Female Cynomolgus Monkeys Dosed with Tamoxifen for 30 Days Cancer Res., September 15, 2003; 63(18): 5999 - 6003. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Shibutani, N. Suzuki, Y. R. S. Laxmi, L. J. Schild, R. L. Divi, A. P. Grollman, and M. C. Poirier Identification of Tamoxifen-DNA Adducts in Monkeys Treated with Tamoxifen Cancer Res., August 1, 2003; 63(15): 4402 - 4406. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. C. Poirier and L. J. Schild The Genotoxicity of Tamoxifen: Extent and Consequences, Kona, Hawaii, January 23, 2003 Mutagenesis, July 1, 2003; 18(4): 395 - 399. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Gamboa da Costa, L.P. McDaniel-Hamilton, R. H. Heflich, M.M. Marques, and F. A. Beland DNA adduct formation and mutant induction in Sprague-Dawley rats treated with tamoxifen and its derivatives Carcinogenesis, August 1, 2001; 22(8): 1307 - 1315. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. H. Phillips Understanding the genotoxicity of tamoxifen? Carcinogenesis, June 1, 2001; 22(6): 839 - 849. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. N.H. White, P. Carthew, R. Davies, J. Styles, K. Brown, J. E. Brown, L. L. Smith, and E. A. Martin Short-term dosing of {{alpha}}-hydroxytamoxifen results in DNA damage but does not lead to liver tumours in female Wistar/Han rats Carcinogenesis, April 1, 2001; 22(4): 553 - 557. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Shibutani, A. Ravindernath, N. Suzuki, I. Terashima, S. M. Sugarman, A. P. Grollman, and M. L. Pearl Identification of tamoxifen-DNA adducts in the endometrium of women treated with tamoxifen Carcinogenesis, August 1, 2000; 21(8): 1461 - 1467. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Shibutani, J. T. Reardon, N. Suzuki, and A. Sancar Excision of Tamoxifen-DNA Adducts by the Human Nucleotide Excision Repair System Cancer Res., May 1, 2000; 60(10): 2607 - 2610. [Abstract] [Full Text]
|
|
|
|
|
|
P. Carthew, R. E. Edwards, B. M. Nolan, E. A. Martin, R. T. Heydon, I. N.H. White, and M. J. Tucker Tamoxifen induces endometrial and vaginal cancer in rats in the absence of endometrial hyperplasia Carcinogenesis, April 1, 2000; 21(4): 793 - 797. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Bartsch, D. H. Phillips, J. Nair, A. Hewer, G. Meyberg-Solomeyer, and E.-M. Grischke Lack of evidence for tamoxifen- and toremifene-DNA adducts in lymphocytes of treated patients Carcinogenesis, April 1, 2000; 21(4): 845 - 847. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. L. Divi, M. R. Osborne, A. Hewer, D. H. Phillips, and M. C. Poirier Tamoxifen-DNA Adduct Formation in Rat Liver Determined by Immunoassay and 32P-Postlabeling Cancer Res., October 1, 1999; 59(19): 4829 - 4833. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. N.H. White The tamoxifen dilemma Carcinogenesis, July 1, 1999; 20(7): 1153 - 1160. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 V. C. Jordan and M. Morrow Tamoxifen, Raloxifene, and the Prevention of Breast Cancer Endocr. Rev., June 1, 1999; 20(3): 253 - 278. [Abstract] [Full Text]
|
|
|
|
|
|
F. Sauvez, D. S. Drouin, M. Attia, H. Bertheux, and R. Forster Cutaneously applied 4-hydroxytamoxifen is not carcinogenic in female rats Carcinogenesis, May 1, 1999; 20(5): 843 - 850. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Berliere, C. Galant, and J. Donnez Case Report:The potential oncogenic effect of tamoxifen on the endometrium Hum. Reprod., May 1, 1999; 14(5): 1381 - 1383. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. M. O'Regan and V. C. Jordan RESPONSE: Re: Effects of the Antiestrogens Tamoxifen, Toremifene, and ICI 182,780 on Endometrial Cancer Growth J Natl Cancer Inst, April 21, 1999; 91(8): 722a - 723a. [Full Text] [PDF]
|
|
|
|
|
|
P. L. Carmichael, S. Sardar, N. Crooks, P. Neven, I. Van Hoof, A. Ugwumadu, T. Bourne, E. Tomas, P. Hellberg, A. J. Hewer, et al. Lack of evidence from HPLC 32P-post-labelling for tamoxifen–DNA adducts in the human endometrium Carcinogenesis, February 1, 1999; 20(2): 339 - 342. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. I. Macgregor and V. C. Jordan Basic Guide to the Mechanisms of Antiestrogen Action Pharmacol. Rev., June 1, 1998; 50(2): 151 - 196. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
