This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Greaves, P. Articles by Orton, T. Search for Related Content PubMed PubMed Citation Articles by Greaves, P. Articles by Orton, T.

Two-Year Carcinogenicity Study of Tamoxifen in Alderley Park Wistar-derived Rats

Safety of Medicines Department, ZENECA Pharmaceuticals, Mereside, Alderley Park, Macclesfield, Cheshire, United Kingdom

Tamoxifen, a nonsteroidal antiestrogen used widely in the treatment of breast cancer, was tested in a conventional 2-year carcinogenicity bioassay in rats, a species in which tamoxifen acts variably as a partial agonist and antagonist on different target tissues. Groups of 51 males and 52 females were given 5, 20, and 35 mg/kg of tamoxifen/day by gastric intubation in 0.5% hydroxypropyl methylcellulose at 5 ml/kg dose volume. There were 102 male and 104 female controls dosed with vehicle alone.

Growth rate and food consumption were reduced in all treated groups. The major finding was a dose-related increase in the incidence of hepatocellular tumors which were first observed after 31 weeks of treatment in the top dose group. The majority of the neoplasms were hepatocellular carcinomas showing a well differentiated trabecular pattern. Some tumors were glandular in type. Mortality was increased in the 20 and 35 mg/kg dose groups compared with controls as a result of these tumors. By contrast, survival was greater than controls in rats given 5 mg/kg tamoxifen despite the presence of hepatocellular tumors due to a reduction in the number of pituitary tumors in females and less chronic renal disease in males.

The mechanism of hepatic tumor induction by tamoxifen in rats is unclear. In view of the lack of genotoxic activity in conventional genotoxicity studies and lack of similar effect in mice or in humans, the findings may relate to a particular constellation of effects in rats. All other drug-induced changes in this study were nonneoplastic in nature and most appeared to be the result of hormonal perturbation since they were confined to endocrine organs or have been seen previously in rats treated for long periods with tamoxifen.

Received 3/22/93. Accepted 6/28/93.

This article has been cited by other articles:

				V. C. Jordan The 38th David A. Karnofsky Lecture: The Paradoxical Actions of Estrogen in Breast Cancer--Survival or Death? J. Clin. Oncol., June 20, 2008; 26(18): 3073 - 3082. [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]

				J. N. Lucas, D. G. Rudmann, K. M. Credille, A. R. Irizarry, A. Peter, and P. W. Snyder The Rat Mammary Gland: Morphologic Changes as an Indicator of Systemic Hormonal Perturbations Induced by Xenobiotics Toxicol Pathol, February 1, 2007; 35(2): 199 - 207. [Abstract] [Full Text] [PDF]

				V. P. Tryndyak, L. Muskhelishvili, O. Kovalchuk, R. Rodriguez-Juarez, B. Montgomery, M. I. Churchwell, S. A. Ross, F. A. Beland, and I. P. Pogribny Effect of long-term tamoxifen exposure on genotoxic and epigenetic changes in rat liver: implications for tamoxifen-induced hepatocarcinogenesis Carcinogenesis, August 1, 2006; 27(8): 1713 - 1720. [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]

				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]

				W. J. Waddell, N. H. Crooks, and P. L. Carmichael Correlation of Tumors with DNA Adducts from Methyl Eugenol and Tamoxifen in Rats Toxicol. Sci., May 1, 2004; 79(1): 38 - 40. [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]

				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]

				E. V. Jensen and V. C. Jordan The Estrogen Receptor: A Model for Molecular Medicine Clin. Cancer Res., June 1, 2003; 9(6): 1980 - 1989. [Abstract] [Full Text] [PDF]

				V. C. Jordan and M. Morrow Re: Trends in Use of Adjuvant Multi-Agent Chemotherapy and Tamoxifen for Breast Cancer in the United States: 1975-1999 J Natl Cancer Inst, May 7, 2003; 95(9): 683 - 684. [Full Text] [PDF]

				S. Maiti and G. Chen Tamoxifen Induction of Aryl Sulfotransferase and Hydroxysteroid Sulfotransferase in Male and Female Rat Liver and Intestine Drug Metab. Dispos., May 1, 2003; 31(5): 637 - 644. [Abstract] [Full Text] [PDF]

				M. Yadollahi-Farsani, D. S. Davies, and A. R. Boobis The mutational signature of {alpha}-hydroxytamoxifen at Hprt locus in Chinese hamster cells Carcinogenesis, November 1, 2002; 23(11): 1947 - 1952. [Abstract] [Full Text] [PDF]

				L. M. Ickenstein and S. M. Bandiera Persistent Suppression of Hepatic CYP2A1 Expression and Serum Triiodothyronine Levels by Tamoxifen in Intact Female Rats: Dose-Response Analysis and Comparison with 4-Hydroxytamoxifen, Fulvestrant (ICI 182,780), and 17beta -Estradiol-3-benzoate J. Pharmacol. Exp. Ther., August 1, 2002; 302(2): 584 - 593. [Abstract] [Full Text] [PDF]

				E. Galbiati, P. L. Caruso, G. Amari, E. Armani, S. Ghirardi, M. Delcanale, and M. Civelli J. Pharmacol. Exp. Ther., March 1, 2002; 300(3): 802 - 809. [Abstract] [Full Text] [PDF]

				T. Kasahara, M. Hashiba, T. Harada, and M. Degawa Change in the gene expression of hepatic tamoxifen-metabolizing enzymes during the process of tamoxifen-induced hepatocarcinogenesis in female rats Carcinogenesis, March 1, 2002; 23(3): 491 - 498. [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]

				P. W. Fan and J. L. Bolton Bioactivation of Tamoxifen to Metabolite E Quinone Methide: Reaction with Glutathione and DNA Drug Metab. Dispos., June 1, 2001; 29(6): 891 - 896. [Abstract] [Full Text]

				D. H. Phillips Understanding the genotoxicity of tamoxifen? Carcinogenesis, June 1, 2001; 22(6): 839 - 849. [Abstract] [Full Text] [PDF]

				S. Shibutani, A. Ravindernath, I. Terashima, N. Suzuki, Y. R. Santosh Laxmi, Y. Kanno, M. Suzuki, T. I. Apak, J. J. Sheng, and M. W. Duffel Mechanism of Lower Genotoxicity of Toremifene Compared with Tamoxifen Cancer Res., May 1, 2001; 61(10): 3925 - 3931. [Abstract] [Full Text]

				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]

				R. Clarke, F. Leonessa, J. N. Welch, and T. C. Skaar Cellular and Molecular Pharmacology of Antiestrogen Action and Resistance Pharmacol. Rev., March 1, 2001; 53(1): 25 - 72. [Abstract] [Full Text] [PDF]

				A. Umemoto, Y. Monden, M. Suwa, Y. Kanno, M. Suzuki, C.-X. Lin, Y. Ueyama, Md.A. Momen, A. Ravindernath, S. Shibutani, et al. Identification of hepatic tamoxifen-DNA adducts in mice: {alpha}-(N2-deoxyguanosinyl)tamoxifen and {alpha}-(N2-deoxyguanosinyl)tamoxifen N-oxide Carcinogenesis, September 1, 2000; 21(9): 1737 - 1744. [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]

				W. Davis, A. Hewer, K. M. Rajkowski, W. Meinl, H. Glatt, and D. H. Phillips Sex Differences in the Activation of Tamoxifen to DNA Binding Species in Rat Liver in Vivo and in Rat Hepatocytes in Vitro: Role of Sulfotransferase Induction Cancer Res., June 1, 2000; 60(11): 2887 - 2891. [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]

				K. P. Nephew, E. Osborne, R. A. Lubet, C. J. Grubbs, and S. A. Khan Effects of Oral Administration of Tamoxifen, Toremifene, Dehydroepiandrosterone, and Vorozole on Uterine Histomorphology in the Rat Experimental Biology and Medicine, March 1, 2000; 223(3): 288 - 294. [Abstract] [Full Text]

				I. Linkov, M. Polkanov, A. Shagiakhmetov, R. Wilson, and G. M. Gray Correlations among tumor types in mouse cancer bioassays: liver adenomas, liver carcinomas, leukemias and lymphomas Toxicology and Industrial Health, February 1, 2000; 16(1): 16 - 40. [Abstract] [PDF]

				Q. Qu, H. Zheng, J. Dahllund, A. Laine, N. Cockcroft, Z. Peng, M. Koskinen, K. Hemminki, L. Kangas, K. Vaananen, et al. Selective Estrogenic Effects of a Novel Triphenylethylene Compound, FC1271a, on Bone, Cholesterol Level, and Reproductive Tissues in Intact and Ovariectomized Rats Endocrinology, February 1, 2000; 141(2): 809 - 820. [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]

				D. H. Phillips, A. Hewer, M. N. Horton, K. J. Cole, P. L. Carmichael, W. Davis, and M. R. Osborne N-Demethylation accompanies {alpha}-hydroxylation in the metabolic activation of tamoxifen in rat liver cells Carcinogenesis, October 1, 1999; 20(10): 2003 - 2009. [Abstract] [Full Text] [PDF]

				K. Brown, R. T. Heydon, R. Jukes, I. N.H. White, and E. A. Martin Further characterization of the DNA adducts formed in rat liver after the administration of tamoxifen, N-desmethyltamoxifen or N,N-didesmethyltamoxifen Carcinogenesis, October 1, 1999; 20(10): 2011 - 2016. [Abstract] [Full Text] [PDF]

				R. M. Bigsby, H. Cardenas, A. Caperell-Grant, and C. J. Grubbs Protective effects of estrogen in a rat model of age-related cataracts PNAS, August 3, 1999; 96(16): 9328 - 9332. [Abstract] [Full Text] [PDF]

				I. N.H. White The tamoxifen dilemma Carcinogenesis, July 1, 1999; 20(7): 1153 - 1160. [Abstract] [Full Text] [PDF]

				R. Davies, T. W. Gant, L. L. Smith, and J. A. Styles Tamoxifen induces G:C->T:A mutations in the cII gene in the liver of lambda/lacI transgenic rats but not at 5'-CpG-3' dinucleotide sequences as found in the lacI transgene Carcinogenesis, July 1, 1999; 20(7): 1351 - 1356. [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]

				I. Terashima, N. Suzuki, and S. Shibutani Mutagenic Potential of {{alpha}}-(N2-Deoxyguanosinyl)tamoxifen Lesions, the Major DNA Adducts Detected in Endometrial Tissues of Patients Treated with Tamoxifen Cancer Res., May 1, 1999; 59(9): 2091 - 2095. [Abstract] [Full Text] [PDF]

				F. A. Beland, L. P. McDaniel, and M. M. Marques Comparison of the DNA adducts formed by tamoxifen and 4-hydroxytamoxifen in vivo Carcinogenesis, March 1, 1999; 20(3): 471 - 477. [Abstract] [Full Text] [PDF]

				M. R. Osborne, A. Hewer, W. Davis, A. J. Strain, A. Keogh, I. R. Hardcastle, and D. H. Phillips Idoxifene derivatives are less reactive to DNA than tamoxifen derivatives, both chemically and in human and rat liver cells Carcinogenesis, February 1, 1999; 20(2): 293 - 297. [Abstract] [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]