Chemoprevention of Breast Cancer by Tamoxifen: Risks and Opportunities

REFERENCES

• Baum, M., Tamoxifen — The treatment of choice. Why look for alternatives? Br J Cancer, 78: 1–4, 1998.
   PubMedGoogle Scholar
• Anon., Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy. 133 randomised trials involving 31000 recurrences and 24000 deaths among 75000 women. Lancet, 339: 1–15, 1992.
   Google Scholar
• , Early Breast Cancer Trialist' Collaborative Group (EBCTCG), Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy. Lancet, 339: 1–15, 1992.
   PubMedGoogle Scholar
• Fisher, B., Dignam, J., Bryant, J., DeCillis, A., Wickerham, D. L., Wolmark, N., Costantino, J., Redmond, C., Fisher, E. R., Bowman, D. M., Deschěnes, L., Dimitrov, N. V., Margolese, R. G., Robidoux, A., Shibata, H., Terz, J., Paterson, A. H. G., Feldman, M. I., Farrar, W., Evans, J., Lickley, H. L., Deschenes, L., et al, Five versus more than five years of tamoxifen therapy for breast cancer patients with negative lymph nodes and estrogen receptor-positive tumors, J Natl Cancer Inst, 88: 1529–1542, 1996.
   PubMed Web of Science ®Google Scholar
• Ruenitz, P. C., Drugs for osteoporosis prevention: mechanisms of bone maintenance. Curr Med Chem, 2: 791–802, 1995.
   Web of Science ®Google Scholar
• Gylling, H., Pyrhönen, S., Mäntylä, E., Mäenpää, H., Kangas, L., and Miettinen, T. A., Tamoxifen and toremifene lower serum cholesterol by inhibition of Deltas8—cholestenol conversion to lathosterol in women with breast cancer. J Clin Oncol, 13: 2900–2905, 1995.
   PubMed Web of Science ®Google Scholar
• Blackwood, M. A. and Weber, B. L., BRCA1 and BRCA2: From molecular genetics to clinical medicine. J Clin Oncol, 16: (pp. 1969–1977), 1998.
   PubMed Web of Science ®Google Scholar
• Powles, T. J., The case for clinical trials of tamoxifen for prevention of breast cancer. Lancet, 340: 1145–1147, 1992.
   PubMedGoogle Scholar
• Fisher, B., Costantino, J. P., Wickerham, D. L., Redmond, C. K., Kavanah, M., Cronin, W. M., Vogel, V., Robidoux, A., Dimitrov, N., Atkins, J., Daly, M., Wieand, S., TanChiu, E., Ford, L., and Wolmark, N., Tamoxifen for prevention of breast cancer: Report of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst, 90: 1371–1388, 1998.
   PubMed Web of Science ®Google Scholar
• Powles, T., Eeles, R., Ashley, S., Easton, D., Chang, J., Dowsett, M., Tidy, A., Viggers, J., and Davey, J., Interim analysis of the incidence of breast cancer in the Royal Marsden Hospital tamoxifen randomised chemo-prevention trial. Lancet, 352: 98–101, 1998.
   PubMed Web of Science ®Google Scholar
• Veronesi, U., Maisonneuve, P., Costa, A., Sacchini, V., Maltoni, C, Robertson, C., Rotmensz, N., and Boyle, P., Prevention of breast cancer with tamoxifen: Preliminary findings from the Italian randomised trial among hysterectomised women. Lancet, 352: 93–97, 1998.
   PubMed Web of Science ®Google Scholar
• Jones, A. L., Powles, T. J., Treleaven, J. G., Burman, J. F., Nicolson, M. C., Chung, H. I. and Ashley, S. E., Haemostatic changes and thromboembolic risk during tamoxifen therapy in normal women. Br J Cancer, 66: 744–747, 1992.
   Google Scholar
• Fornander, T., Cedermark, B., Mattsson, A., Skoog, L., Theve, T., Askergren, J., Rutqvist, L. E., Glas, D., Silfversward, C., Somell Wilking, N. and Hjalmar, M., Adjuvant tamoxifen in early breast cancer: occurrence of new primary cancers. Lancet, 1: 117–119, 1989.
   PubMed Web of Science ®Google Scholar
• Rutqvist, L. E., Johansson, H., Signomklao, T., Johansson, U., Fornander, T. and Wilking, N., Adjuvant tamoxifen therapy for early stage breast cancer and second primary malignancies. Stockholm Breast Cancer Study Group. J Natl Cancer Inst, 87: 645–651, 1995.
   PubMed Web of Science ®Google Scholar
• Fisher, B., Costantino, J. P., Redmond, C. K., Fisher, E. R., Wickerham, D. L., Cronin, W. M., and NSABP Contributors, Endometrial cancer in tamoxifen-treated breast cancer patients: Findings from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-14. J Natl Cancer Inst, 86: 527–537, 1994.
   PubMed Web of Science ®Google Scholar
• Curtis, R. E., Boice, J. D., Jr., Shriner, D. A., Hankey, B. F. and Fraumeni, J. F., Jr., Second cancers after adjuvant tamoxifen therapy for breast cancer. J Natl Cancer Inst, 88: 832–834, 1996.
   PubMed Web of Science ®Google Scholar
• Tamoxifen, in Some Pharmaceutical Drugs. IARC: Lyon, France, 1996. pp. 253–365.
   Google Scholar
• Greaves, P., Goonetilleke, R., Nunn, G., Topham, J., and Orton, T., Two-year carcinogenicity study of tamoxifen in Alderly Park Wistar-derived rats. Cancer Res, 53: 3919–3924, 1993.
   PubMed Web of Science ®Google Scholar
• Williams, G. M., Iatropoulos, M. J., Djordjevic, M. V., and Kaltenberg, O. P., The triphenylethylene drug tamoxifen is a strong liver carcinogen in the rat. Carcinogenesis, 14: 315–317, 1993.
   PubMed Web of Science ®Google Scholar
• Hirsimaki, P., Hirsimaki, Y., Nieminen, L. and Payne, B. J., Tamoxifen induces hepato-cellular carcinoma in rat liver — a 1-year study with 2 antiestrogens. Arch Toxicol, 67: 49–54, 1993.
   PubMed Web of Science ®Google Scholar
• Carthew, P., Martin, E. A., White, I. N. H., De Matteis, F., Edwards, R. E., Dorman, B. M., Heydon, R. T., and Smith, L. L., Tamoxifen induces short-term cumulative DNA damage and liver tumors in rats: promotion by phenobarbital. Cancer Res, 55: 544–547, 1995.
   PubMed Web of Science ®Google Scholar
• Ghia, M. and Mereto, E., Induction and promotion of gamma — glutamyltranspeptidase-positive foci in the liver of female rats treated with ethinyl estradiol, clomiphene, tamoxifen and their associations. Cancer Lett, 46: 195–202, 1989.
   Google Scholar
• Dragan, Y. P., Shimel, R. J., Bahnub, N., Sattler, G., Vaughan, J. R., Jordan, V. C., and Pitot, H. C., Effect of chronic administration of mestranol, tamoxifen, and toremifene on hepatic ploidy in rats. Toxicol Sci, 43: 129–138, 1998.
   Google Scholar
• Carthew, P., Rich, K. J., Martin, E. A., De Matteis, F., Lim, C. K., Manson, M. M., Festing, M. F., White, I. N., and Smith, L. L., DNA damage as assessed by 32P-postlabelling in three rat strains exposed to dietary tamoxifen: the relationship between cell proliferation and liver tumor formation. Carcinogenesis, 16: 1299–1304, 1995.
   PubMed Web of Science ®Google Scholar
• Carthew, P., Nolan, B. M., Edwards, R. E., and Smith, L. L., The role of cell death and cell proliferation in the promotion of rat liver tumours by tamoxifen. Cancer Lett, 106: 163–169, 1996.
   Google Scholar
• Hard, G. C., Iatropoulos, M. J., Jordan, K., Radi, L., Kaltenberg, O. P., Imondi, A. R., and Williams, G. M., Major differences in the hepatocarcinogenicity and DNA adduct forming ability between toremifene and tamoxifen in female Cr1: CD(BR) rats. Cancer Res, 53: 4534–4541, 1993.
   PubMed Web of Science ®Google Scholar
• Williams, G. M., Iatropoulos, M. J., and Karlsson, S., Initiating activity of the anti-estrogen tamoxifen, but not toremifene in rat liver. Carcinogenesis, 18, 2247–2253, 1997.
   PubMed Web of Science ®Google Scholar
• Carthew, P., Edwards, R. E., and Nolan, B. M., Depletion of hepatocyte nuclear estrogen receptor expression is associated with promotion of tamoxifen induced GST-P foci to tumours in rat liver. Carcinogenesis, 18: 1109–1112, 1997.
   Google Scholar
• Eagon, P. K., Francavilla, A., DiLeo, A., Elm, M. S., Gennari, L., Mazzoferro, V., Colella, G., Van Thiel, D. H., and Starzl, T. E., Quantitation of estrogen and androgen receptors in hepatocellular carcinoma and adjacent normal human liver. Dig Dis Sci, 36: 1303–1308, 1991.
   Google Scholar
• Chaidarun, S. S. and Alexander, J. M., A tumor-specific truncated estrogen receptor slice variant enhances estrogen-stimulated gene expression. Mol Endocrinol, 12: 1355–1366, 1998.
   Google Scholar
• Paech, K., Webb, P., Kuiper, G. G. J. M., Nilsson, S., Gustafsson, J. Å., Kushner, P. J. and Scanlan, T. S., Differential ligand activation of estrogen receptors ERα and ERβ at AP1 sites. Science, 277: 1508–1510, 1997.
   PubMed Web of Science ®Google Scholar
• Jones, P. S., Parrott, E., and White, I. N. H., Activation of transcription by estrogen receptor alpha and beta is cell type- and promoter-dependent. J Biol Chem, 274: 32008–32014, 1999.
   PubMedGoogle Scholar
• Dahme, E. and Rattel, B., Unlike tamoxifen, droloxifene produces no hepatic tumors in the rat. Onkologie, 17: 6–16, 1994.
   Google Scholar
• Li, D., Dragan, Y., Jordan, V. C., Wang, M. and Pitot, H. C., Effects of chronic administration of tamoxifen and toremifene on DNA adducts in rat liver, kidney, and uterus. Cancer Res, 57: 1438–1441, 1997.
   PubMed Web of Science ®Google Scholar
• Tucker, M. J., Adams, H. K., and Patterson, J. S., Tamoxifen, in Safety Testing of New Drugs, Laurence, D. R., McLean, A. E. M., Weatherall, M. Eds., Academic Press, New York, 1984, pp. 125–161.
   Google Scholar
• Martin, E. A., Carthew, P., White, I. N. H., Heydon, R. T., Gaskell, M., Mauthe, R. J., Turteltaub, K. W., and Smith, L. L., Investigation of the formation and accumulation of liver DNA adducts in mice chronically exposed to tamoxifen. Carcinogenesis, 18: 2209–2215, 1997.
   PubMed Web of Science ®Google Scholar
• Newbold, R. R., Jefferson, W. N., PadillaBurgos, E. and Bullock, B. C., Uterine carcinoma in mice treated neonatally with tamoxifen. Carcinogenesis, 18: 2293–2298, 1997.
   PubMed Web of Science ®Google Scholar
• Diwan, B. A., Anderson, L. M., and Ward, J. M., Proliferative lesions of oviduct and uterus in CD-1 mice exposed prenatally to tamoxifen. Carcinogenesis, 18: 2009–2014, 1997.
   Google Scholar
• Carthew, P., Edwards, R. E., Nolan, B. M., Martin, E. A. and Smith, L. L., Tamoxifen-associated uterine pathology in rodents: relevance to women. Carcinogenesis, 17: 1577–1582, 1996.
   PubMed Web of Science ®Google Scholar
• Mantyala, E. T. E., Karlsson, S. H., and Nieminen, L. S., in Hormonal Carcinogenesis 2. Proceedings of the Second International Symposium, Li, J. J., Li, S. A., Gustafsson, J. A., Nandi, S., Sekely, L. I., Eds., Springer-Verlag, New York, 1998, pp. 442–445.
   Google Scholar
• Carthew, P., Edwards, R. E., Nolan, B. M., Martin, E. A., Heydon, R. T., White, I. N. H., and Tucker, M. J., Tamoxifen induces endometrial and vaginal cancer in rats in the absence of endometrial hyperplasia. Carcinogenesis, 21: 793–797, 2000.
   PubMed Web of Science ®Google Scholar
• Han, X. and Liehr, J. G., Induction of covalent DNA adducts in rodents by tamoxifen. Cancer Res, 52: 1360–1363, 1992.
   PubMed Web of Science ®Google Scholar
• White, I. N. H., De Matteis, F., Davies, A. M., Smith, L. L., Crofton-Sleigh, C., Venitt, S., Hewer, A., and Phillips, D. H., Genotoxic potential of tamoxifen and analogues in female Fischer F344/N rats, DBA/2 and C57B1/6 mice and in human MCL-5 cells. Carcinogenesis, 13: 2197–2203, 1992.
   PubMed Web of Science ®Google Scholar
• Martin, E. A., Heydon, R. T., Brown, K., Brown, J. E., Lim, C. K., White, I. N., and Smith, L. L., Evaluation of tamoxifen and alpha-hydroxytamoxifen 32p-post-labelled DNA adducts by the development of a novel automated on-line solid-phase extraction HPLC method. Carcinogenesis, 19: 1061–1069, 1998.
   PubMed Web of Science ®Google Scholar
• Randerath, K., Bi, J., Mabon, N., Sriram, P., and Moorthy, B., Strong intensification of mouse hepatic tamoxifen DNA adduct formation by pretreatment with the sulfotransferase inhibitor and ubiquitous environmental pollutant pentachlorophenol. Carcinogenesis, 15: 797–800, 1994.
   PubMed Web of Science ®Google Scholar
• Montandon, F. and Williams, G. M., Comparison of DNA reactivity of the polyphenylethylene hormonal agents diethylstilbestrol, tamoxifen and toremifene in rat and hamster liver. Arch Toxicol, 68: 272–275, 1994.
   PubMed Web of Science ®Google Scholar
• Randerath, K., Moorthy, B., Mabon, N., and Sriram, P., Tamoxifen: evidence by 32p-postlabeling and use of metabolic inhibitors for two distinct pathways leading to mouse hepatic DNA adduct formation and identification of 4-hydroxytamoxifen as a proximate metabolite. Carcinogenesis, 15: 2089–2094, 1994.
   Google Scholar
• Rajaniemi, H., Mäntylä, E., and Hemminki, K., DNA adduct-formation by tamoxifen and structurally related compounds in rat liver. Chem Biol Interact, 113: 145–159, 1998.
   PubMed Web of Science ®Google Scholar
• Pathak, D. N., Pongracz, K., and Bodell, W. J., Activation of 4-hydroxytamoxifen and the tamoxifen derivative metabolite E by uterine peroxidase to form DNA adducts: Comparison with DNA adducts formed in the uterus of Sprague-Dawley rats treated with tamoxifen. Carcinogenesis, 17: 1785–1790, 1996.
   PubMed Web of Science ®Google Scholar
• White, I. N. H., Martin, E. A., Vogel, J. S., Mauthe, R. J., Turteltaub, K. W., and Smith, L. L., Comparison of the binding of [14C]radiolabelled tamoxifen or toremifene to rat DNA using accelerator mass spectrometry. Chem Biol Interact, 106: 149–160, 1997.
   PubMedGoogle Scholar
• Phillips, D. H., Carmichael, P. L., Hewer, A., Cole, K. J., Hardcastle, I. R., Poon, G. K., Strain, A. J., and Keogh, A., Activation of tamoxifen and its metabolite a-hydro-xytamoxifen to DNA-binding products: Comparisons between human, rat and mouse hepatocytes. Carcinogenesis, 17: 89–94, 1996.
   PubMed Web of Science ®Google Scholar
• Davis, W., Venitt, S., and Phillips, D. H., The metabolic activation of tamoxifen and alpha-hydroxytamoxifen to DNA-binding species in rat hepatocytes proceeds via sulfation. Carcinogenesis, 19: 861–866, 1998.
   PubMed Web of Science ®Google Scholar
• Hemminki, K., Rajaniemi, H., Koskinen, M., and Hansson, J., Tamoxifen-induced DNA adducts in leukocytes of breast cancer patients. Carcinogenesis, 18: 9–13, 1997.
   PubMed Web of Science ®Google Scholar
• Phillips, D. H., Hewer, A., Grover, P. L., Poon, G. K., and Carmichael, P. L., Tamoxifen does not form detectable DNA adducts in white blood cells of breast cancer patients. Carcinogenesis, 17: 1149–1152, 1996.
   PubMed Web of Science ®Google Scholar
• Hemminki, K., Widlak, P., and Hou, S. M., DNA adducts caused by tamoxifen and toremifene in human microsomal system and lymphocytes in vitro. Carcinogenesis, 16: 1661–1664, 1995.
   PubMed Web of Science ®Google Scholar
• Pathak, D. N. and Bodell, W. J., DNA adduct formation by tamoxifen with rat and human liver microsomal activation systems. Carcinogenesis, 15: 529–532, 1994.
   PubMed Web of Science ®Google Scholar
• Pongracz, K., Pathak, D. N., Nakamura, T., Burlingame, A. L., and Bodell, W. J., Activation of the tamoxifen derivative metabolite E to form DNA adducts: comparison with the adducts formed by microsomal activation of tamoxifen. Cancer Res, 55: 3012–3015, 1995.
   Google Scholar
• Moorthy, B., Sriram, P., Pathak, D. N., Bodell, W. J., and Randerath, K., Tamoxifen metabolic activation: comparison of DNA adducts formed by microsomal and chemical activation of tamoxifen and 4-hydroxytamoxifen with DNA adducts formed in vivo. Cancer Res, 56: 53–57, 1996.
   PubMed Web of Science ®Google Scholar
• Davies, A. M., Martin, E. A., Jones, R. M., Lim, C. K., Smith, L. L., and White, I. N., Peroxidase activation of tamoxifen and toremifene resulting in DNA damage and covalently bound protein adducts. Carcinogenesis, 16: 539–545, 1995.
   PubMed Web of Science ®Google Scholar
• Martin, E. A., Rich, K., White, I. N. H., Woods, K. L., Powles, T. J., and Smith, L. L., 32P-Postlabelled DNA adducts in liver obtained from women treated with tamoxifen. Carcinogenesis, 16: 1651–1654, 1995.
   PubMed Web of Science ®Google Scholar
• Carmichael, P. L., Ugwumadu, A. H. N., Neven, P., Hewer, A. J., Poon, G. K., and Phillips, D. H., Lack of genotoxicity of tamoxifen in human endometrium. Cancer Res, 56: 1475–1479, 1996.
   PubMed Web of Science ®Google Scholar
• Carmichael, P. L., Neven, P., Sardar, S., VanHoof, I., Ugwumadu, A., Bourne, T., Tomas, E., Hellberg, P., Hewer, A., Davis, W., and Phillips, D. H., A lack of evidence for the genotoxicity of tamoxifen and toremifene in the human endometrium. Eur J Cancer, 34: P106, 1998.
   Google Scholar
• Hemminki, K., Rajaniemi, H., Lindahl, B., and Moberger, B., Tamoxifen-induced DNA adducts in endometrial samples from breast cancer patients. Cancer Res, 56: 4374–4377, 1996.
   PubMed Web of Science ®Google Scholar
• Shibutani, S., Suzuki, N., Terashima, I., Sugarman, S. M., Grollman, A. P., and Pearl, M. L., Tamoxifen-DNA adducts detected in the endometrium of women treated with tamoxifen. Chem Res Toxicol, 12: 646–653, 1999.
   PubMed Web of Science ®Google Scholar
• Karki, N. T. and Karki, T., Cytogenic effects of a novel antiestrogen toremifene FC-1157a: a comparison with diethylstilbestrol and tamoxifen. Arch Toxicol, 59: (Suppl.), 9, 1986.
   Google Scholar
• Styles, J. A., Davies, A. M., White, I. N. H., and Stanley, L. A., Studies on the mutagenicity of tamoxifen. Hum Exp Toxicol, 12: 570–570, 1993.
   Google Scholar
• Branda, R. F., Oneill, J. P., Sullivan, L. M., and Albertini, R. J., Factors influencing mutation at the hprt locus in T-lymphocytes: women treated for breast cancer. Cancer Res, 51: 6603–6607, 1991.
   Google Scholar
• Davies, R., Oreffo, V. I. C., Bayliss, S., Dinh, P-A., Lilley, K. S., White, I. N. H., Smith, L. L., and Styles, J. A., Mutational spectra of tamoxifen-induced mutations in the livers of lacI transgenic rats. Env Mol Mutagenesis, 28: 430–433, 1996.
   PubMed Web of Science ®Google Scholar
• Davies, R., Oreffo, V. I. C., Martin, E. A., Festing, M., White, I. N. H., Smith, L. L., and Styles, J. A., Tamoxifen causes gene mutations in the livers of lambda/lacI transgenic rats. Cancer Res, 57: 1288–1293, 1997.
   PubMed Web of Science ®Google Scholar
• Styles, J. A., Davies, R., Fenwick, S., Walker, J., Martin, E. A., White, I. N. H., and Smith, L. L., Studies on tamoxifen-induced mutations in the liver and uteri of Big Blue™ transgenic F344 rats. Toxicol Lett, 95: 49, (Suppl), 1, 1998.
   Google Scholar
• Styles, J. A., Davies, R., Fenwick, S., Walker, J., White, I. N. H., and Smith, L. L., Phenobarbital promotion does not influence the frequency of tamoxifen-induced mutations in the livers of Big Blue transgenic F344 rats. The Toxicologist, 42: 9, 1998.
   Google Scholar
• Lowes, D. A., Brown, K., Heydon, R. T., Martin, E. A., and Gant, T. W., Site-specific tamoxifen-DNA adduct formation: Lack of correlation with mutational ability in Escherichia coli. Biochemistry, 38: 10989–10996, 1999.
   PubMed Web of Science ®Google Scholar
• Terashima, I., Suzuki, N., and Shibutani, S., Mutagenic potential of alpha-(N2-deoxyguanosinyl)tamoxifen lesions, the major DNA adducts detected in endometrial tissues of patients treated with tamoxifen. Cancer Res, 59: 2091–2095, 1999.
   PubMed Web of Science ®Google Scholar
• Vancutsem, P. M., Lazarus, P., and Williams, G. M., Frequent and specific mutations of the rat p53 gene in hepatocarcinomas induced by tamoxifen. Cancer Res, 54: 3864–3867, 1994.
   PubMed Web of Science ®Google Scholar
• Hsu, I. C., Metcalf, R. A., Sun, T., Welsh, J. A., Wang, N. J., and Harris, C. C., Mutational hot spot in the p53 gene in human hepatocellular carcinomas. Nature, 350: 427–428, 1991.
   PubMed Web of Science ®Google Scholar
• Bressac, B., Khalid, S., Wands, J., and Ozturk, M., G to T mutations of p53 gene in hepato-cellular carcinomas from Southern Africa. Nature, 350: 429–432, 1991.
   PubMed Web of Science ®Google Scholar
• Welsh, J. A., Moberger, B., Fornander, T., Malfetano, J. H., Ambros, R. A., Weed, J. C., Deligdisch, L., Cohen, C. J., Silva, E. G., Vincent, F., Jones, R. T., and Bennett, W. P., Tamoxifen has a characteristic mutation spectrum in human endometrial cancers. Proc Am Soc Cancer Res, 38: 450–1997.
   Google Scholar
• Kuwashima, Y., Kurosumi, M., Kobayashi, Y., Tanuma, J., Suemasu, K., Higashi, Y., Kasamatsu, T., Shiromizu, K., and Kishi, K., Random nuclear p53 overexpression pattern in tamoxifen-mediated endometrial carcinoma. Int J Gynecol Pathol, 17: 135–139, 1998.
   PubMed Web of Science ®Google Scholar
• Crofton-Sleigh, C., Doherty, A., Ellard, S., Parry, E. M., and Venitt, S., Micronucleus assays using cytochalasin-blocked MCL-5 cells, a proprietary human cell line expressing five human cytochromes P-450 and microsomal epoxide hydrolase. Mutagenesis, 8: 363–372, 1993.
   PubMed Web of Science ®Google Scholar
• Styles, J. A., Davies, A., Lim, C. K., De Matteis, F., Stanley, L. A., White, I. N., Yuan, Z. X., and Smith, L. L., Genotoxicity of tamoxifen, tamoxifen epoxide and toremifene in human lymphoblastoid cells containing human cytochrome P450s. Carcinogenesis, 15: 5–9, 1994.
   PubMed Web of Science ®Google Scholar
• Styles, J. A., Davies, A. M., Davies, R., White, I. N. H., and Smith, L. L., Clastogenic and aneugenic effects of tamoxifen and some of its analogues in hepatocytes from dosed rats and in human lymphoblastoid cells transfected with human P450 cDNAs (MCL-5 cells). Carcinogenesis, 18: 303–313, 1997.
   PubMed Web of Science ®Google Scholar
• Sargent, L., Dragan, Y., Xu, Y. H., Sattler, G., Wiley, J., and Pitot, H. C., Karyotypic changes in a multistage model of chemical hepatocarcinogenesis in the rat. Cancer Res, 56: 2985–2991, 1996.
   PubMed Web of Science ®Google Scholar
• Sargent, L. M., Dragan, Y. P., Bahnub, N., Wiley, J. E., Sattler, C. A., Schroeder, P., Sattler, G. L., Jordan, V. C., and Pitot, H. C., Tamoxifen induces hepatic aneuploidy and mitotic spindle disruption after a single in vivo administration to female Sprague-Dawley rats. Cancer Res, 54: 3357–3360, 1994.
   PubMedGoogle Scholar
• Sargent, L. M., Dragan, Y. P., Sattler, C., Bahnub, N., Sattler, G., Martin, P., Cisneros, A., Mann, J., Thorgeirsson, S., Jordan, V. C., and Pitot, H. C., Induction of hepatic aneuploidy in vivo by tamoxifen, toremifene and idoxifene in female Sprague-Dawley rats. Carcinogenesis, 17: 1051–1056, 1996.
   PubMed Web of Science ®Google Scholar
• Metzler, M. and Schiffmann, D., Structural requirements for the in vitro transformation of Syrian hamster embryo cells by stilbene estrogens and triphenylethylene-type antiestrogens. Am J Clin Oncol, 14: S30–S35, 1991.
   PubMed Web of Science ®Google Scholar
• Jordan, V. C., Allen, K. E., and Dix, C. J., Pharmacology of tamoxifen in laboratory animals. Cancer Treat Rep, 64: 745–758, 1980.
   PubMedGoogle Scholar
• Fromson, J. M., Pearson, S., and Bramah, S., The metabolism of Tamoxifen *(I. C. I. 46,476). I. In laboratory animals. Xenobiotica, 3: 693–703, 1973.
   PubMed Web of Science ®Google Scholar
• Fromson, J. M., Pearson, S., and Bramah, S., Metabolism of tamoxifen (I. C. I. 46, 474) II. In female patients. Xenobiotica, 3: 711–714, 1973.
   PubMed Web of Science ®Google Scholar
• Lyman, S. D. and Jordan, V. C., Metabolism of tamoxifen and its uterotrophic activity. Biochem Pharmacol, 34: 2787–2794, 1995.
   Google Scholar
• Lien, E. A., Solheim, E., Lea, O. A., Lundgren, S., Kvinnsland, S., and Ueland, P. M., Distribution of 4-hydroxy-N-desmethyltamoxifen and other tamoxifen metabolites in human biological fluids during tamoxifen treatment. Cancer Res, 49: 2175–2183, 1989.
   PubMed Web of Science ®Google Scholar
• Ruenitz, P. C., Bagley, J. R., and Pape, C. W., Some chemical and biochemical aspects of liver microsomal metabolism of tamoxifen. Drug Metab Dispos, 12: 478–483, 1985.
   Google Scholar
• Lu, W., Poon, G. K., Carmichael, P. L., and Cole, R. B., Analysis of tamoxifen and its metabolites by on-line capillary electrophoresis—Electrospray ionization mass spectrometry employing nonaqueous media containing surfactants. Anal Chem, 68: 668–674, 1996.
   PubMed Web of Science ®Google Scholar
• Poon, G. K., Cui, Y. C., McCague, R., Lanning, P. E., Feng, R., Rowlands, M. G., and Jarman, M., Analysis of phase 1 and phase 11 metabolites of tamoxifen in breast cancer patients. Drug Metab Dispos, 21: 1119–1194, 1995.
   Google Scholar
• Poon, G. K., Walter, B., Lonning, P. E., Horton, M. N., and McCague, R., Identification of tamoxifen metabolites in human HEP G2 cell line, human liver homogenate, and patients on long-term therapy for breast cancer. Drug Metab Dispos, 23: 377–382, 1995.
   PubMed Web of Science ®Google Scholar
• Adam, H. K., Patterson, J. S., and Kemp, J. V., Studies on the metabolism and pharmacokinetics of tamoxifen in normal volunteers. Cancer Treat Rep, 64: 761–764, 1980.
   PubMedGoogle Scholar
• Fuchs, W. S., Leary, W. P., Van Der Meer, M. J., Gay, S., Witschital, K., and Von Nieciecki, A., Pharmacokinetics and bioavailability of tamoxifen in postmenopausal healthy women. Arzneimittelforschung, 46: 418–422, 1996.
   Google Scholar
• Furr, B. J. A. and Jordan, V. C., The pharmacology and clinical uses of tamoxifen. Pharmacol Ther, 25: 127–205, 1984.
   PubMed Web of Science ®Google Scholar
• Peyrade, F., Frenay, M., Etienne, M. C., Ruch, F., Guillemare, C., Francois, E., Namer, M., Ferrero, J. M., and Milano, G., Age-related difference in tamoxifen disposition. Clin Pharmacol Therap, 59: 401–410, 1996.
   PubMed Web of Science ®Google Scholar
• Lien, E. A., Solheim, E., and Ueland, P. M., Distribution of tamoxifen and its metabolites in rat and human tissues during steady-state treatment. Cancer Res, 51: 4837–4844, 1991.
   PubMed Web of Science ®Google Scholar
• Daniel, C. P., Gaskell, S. J., and Nicholson, R. I., Measurement of tamoxifen and metabolites in the rat and relationship to the response of DMB A-induced mammary tumours. Eur J Cancer Clin Oncol, 20: 137–143, 1984.
   Google Scholar
• Foster, A. B., Griggs, M., Jarman, M., van Maanen, J. M. S., and Schulten, H. R., Metabolism of tamoxifen by rat liver microsomes: formation of the oxide, a new metabolite. Biochem Pharmacol, 29: 1977–1979, 1980.
   PubMed Web of Science ®Google Scholar
• Lim, C. K., Yuan, Z. X., Lamb, J. H., White, I. N., De Matteis, F., and Smith, L. L., A comparative study of tamoxifen metabolism in female rat, mouse and human liver microsomes. Carcinogenesis, 15: 589–593, 1994.
   PubMed Web of Science ®Google Scholar
• Jacolot, F., Simon, I., Dreano, Y., Beaune, P., Riche, C., and Berthou, F., Identification of the cytochrome P450 IIIA family as the enzymes involved in the N-demethylation of tamoxifen in human liver microsomes. Biochem Pharmacol, 41: 1911–1919, 1991.
   PubMed Web of Science ®Google Scholar
• Mani, C., Gelboin, H. V., Park, S. S., Pearce, R., Parkinson, A., and Kupfer, D., Metabolism of the antimammary cancer antiestrogenic agent tamoxifen. I. Cytochrome P-450-cata-lyzed N-demethylation and 4-hydroxylation. Drug Metab Dispos, 21: 645–656, 1993.
   PubMed Web of Science ®Google Scholar
• Mani, C., Hodgson, E., and Kupfer, D., Metabolism of the antimammary cancer antiestrogenic agent tamoxifen. II. Flavin-containing monooxygenase-mediated N-oxidation. Drug Metab Dispos, 21: 657–661, 1993.
   PubMed Web of Science ®Google Scholar
• Daniels, L., Blankson, E. A., Henderson, C. J., Harris, A. H., Wolf, C. R., Lennard, M. S., and Tucker, G. T., Delineation of human cytochromes P450 involved in the metabolism of tamoxifen. Br J Clin Pharmacol, 34: 153P–154P, 1992.
   Google Scholar
• White, I. N. H., De Matteis, F., Gibbs, A. H., Lim, C. K., Wolf, C. R., Henderson, C., and Smith, L. L., Species differences in the covalent binding of [14C]tamoxifen to liver microsomes and the forms of cytochrome P450 involved. Biochem Pharmacol, 49: 1035–1042, 1995.
   PubMed Web of Science ®Google Scholar
• Mani, C., Pearce, R., Parkinson, A., and Kupfer, D., Involvement of cytochrome P4503A in catalysis of tamoxifen activation and covalent binding to rat and human liver microsomes. Carcinogenesis, 15: 2715–2720, 1994.
   PubMed Web of Science ®Google Scholar
• Dehal, S. S. and Kupfer, D., CYP2D6 catalyzes tamoxifen 4-hydroxylation in human liver. Cancer Res, 57: 3402–3406, 1997.
   PubMed Web of Science ®Google Scholar
• White, I. N. H., Davies, A. M., Smith, L. L., Dawson, S., and De Matteis, F., Induction of CYP2B1 and 3A1 and associated monooxygenase activities by tamoxifen and certain analogues in the livers of female rats and mice. Biochem Pharmacol, 45: 21–30, 1993.
   PubMed Web of Science ®Google Scholar
• Nuwaysir, E. F., Dragan, Y. P., McCague, R., Martin, P., Mann, J., Jordan, V. C., and Pitot, H. C., Structure-activity relationships for triphenylethylene antiestrogens on hepatic phase-I and phase-II enzyme expression. Biochem Pharmacol, 56: 321–327, 1998.
   Google Scholar
• Nuwaysir, E. F., Dragan, Y. P., Jeffcoate, C. R., Jordan, V. C., and Pitot, H. C., Effects of tamoxifen administration on the expression of xenobiotic metabolizing enzymes in rat liver. Cancer Res, 55: 1780–1786, 1995.
   Google Scholar
• Robinson, S. P., Langan-Fahey, L., Johnson, D. A., and Jordan, V. C., Metabolites, pharmacodynamics and pharmacokinetics of tamoxifen in rats and mice compared to the breast cancer patient. Drug Metab Dispos, 19: 36–43, 1991.
   PubMedGoogle Scholar
• Davies, A. M., Malone, M. E., Martin, E. A., Jones, R. M., Jukes, R., Lim, C. K., Smith, L. L., and White, I. N. H., Peroxidase activation of 4-hydroxytamoxifen to free radicals detected by EPR spectroscopy. Free Radical Biol Med, 22: 423–431, 1997.
   Google Scholar
• Mani, C. and Kupfer, D., Cytochrome P450 mediated action and irreversible binding of the antiestrogen tamoxifen to proteins in rat and human liver: possible involvement of the flavin-containing monooxygenases in tamoxifen activation. Cancer Res, 51: 6052–6058, 1991.
   PubMed Web of Science ®Google Scholar
• Weibe, V. J., Osborne, C. K., McGuire, W. L., and Degregorio, M. W., Identification of estrogenic tamoxifen metabolite(s) in tamoxifen-resistant human breast tumors. J Clin Oncol, 10: 990–994, 1992.
   Google Scholar
• Jones, R. M., Yuan, Z. X., Lamb, J. H., and Lim, C. K., On-line high-performance liquid chromatographic-electrospray ionization mass spectrometric method for the study of tamoxifen metabolism. J Chromatog A, 722: 249–255, 1996.
   Google Scholar
• Liehr, J. G., Ricci, M. J., Jeffcoate, C. R., Hannigan, E. V., Hokanson, J. A., and Zhu, B. T., 4-hydroxylation of estradiol by human uterine myometrium and myoma microsomes: Implications for the mechanism of uterine tumorigenesis. Proc Natl Acad Sci USA, 92: 9220–9224, 1995.
   PubMed Web of Science ®Google Scholar
• Dehal, S. S. and Kupfer, D., Evidence that the catechol 3,4-dihydroxytamoxifen is a proximate intermediate to the reactive species binding covalently to proteins. Cancer Res, 56: 1283–1290, 1996.
   PubMed Web of Science ®Google Scholar
• Butterworth, M., Jukes, R., Gaskell, M., Heydon, R., Martin, E. A., Smith, L. L., and White, I. N. H., DNA-adducts formed by 3,4-dihydrox-ytamoxifen, a potential reactive metabolite of tamoxifen. The Toxicologist, 42: 78, 1998.
   Google Scholar
• Zhang, F., Fan, P. W., Liu, X., Shen, L., van Breemen, R. B. and Bolton, J. L., Synthesis and reactivity of a potential carcinogenic metabolite of tamoxifen: 3,4-dihydrox-ytamoxifen-o-quinone. Chem Res Toxicol, 13: 53–62, 2000.
   PubMed Web of Science ®Google Scholar
• Fan, P. W., Zhang, F., and Bolton, J. L., 4-Hydroxylated metabolites of the antiestrogens tamoxifen and toremifene are metabolized to unusually stable quinone methides. Chem Res Toxicol, 13: 45–52, 2000.
   PubMed Web of Science ®Google Scholar
• Boocock, D. J., Maggs, J. L., White, I. N. H., and Park, B. K., Alpha-hydroxytamoxifen, a genotoxic metabolite of tamoxifen in the rat: identification and quantification in vivo and in vitro. Carcinogenesis, 20: 153–160, 1999.
   PubMed Web of Science ®Google Scholar
• Potter, G. A., McCague, R., and Jarman, M., A mechanistic hypothesis for DNA adduct formation by tamoxifen following hepatic oxidative metabolism. Carcinogenesis, 15: 439–442, 1994.
   PubMed Web of Science ®Google Scholar
• Jarman, M., Poon, G. K., Rowlands, M. G., Grimshaw, R. M., Horton, M. N., Potter, G. A., and McCague, R., The deuterium isotope effect for the α-hydroxylation of tamoxifen by rat liver microsomes accounts for the reduced genotoxicity of [D5-ethyl]tamoxifen. Carcinogenesis, 16: 683–688, 1995.
   PubMed Web of Science ®Google Scholar
• Phillips, D. H., Carmichael, P. L., Hewer, A., Cole, K. J., and Poon, G. K., α-Hydroxytamoxifen, a metabolite of tamoxifen with exceptionally high DNA binding activity in rat hepatocytes. Cancer Res, 54: 5518–5522, 1995.
   Google Scholar
• Glatt, H., Davis, W., Meinl, W., Hermersdorfer, H., Venitt, S., and Phillips, D. H., Rat but not human sulfotransferase activates a tamoxifen metabolite to produce DNA adducts and gene mutations in bacteria and mammalian cells in culture. Carcinogenesis, 19: 1709–1713, 1998.
   PubMed Web of Science ®Google Scholar
• Shibutani, S., Shaw, P. M., Suzuki, N., Dasaradhi, L., Duffel, M. W., and Terashima, I., Sulfation of α-hydroxytamoxifen catalyzed by human hydroxysteroid sulfotransferase results in tamoxifen-DNA adducts. Carcinogenesis, 19: 2007–2011, 1998.
   PubMed Web of Science ®Google Scholar
• Osborne, M. R., Hewer, A., Hardcastle, I. R., Carmichael, P. L., and Phillips, D. H., Identification of the major tamoxifen-deoxyguanosine adduct formed in the liver DNA of rats treated with tamoxifen. Cancer Res, 56: 66–71, 1996.
   PubMed Web of Science ®Google Scholar
• Dasaradhi, L. and Shibutani, S., Identification of tamoxifen-DNA adducts formed by α-sulfate tamoxifen and α-acetoxytamoxifen. Chem Res Toxicol, 10: 189–196, 1997.
   PubMed Web of Science ®Google Scholar
• Dipple, A., DNA adducts of chemical carcinogens. Carcinogenesis, 16: 437–441, 1995.
   PubMed Web of Science ®Google Scholar
• Phillips, D. H., Miller, J. A., Miller, E. C., and Adams, B. N., N2 atom of guanine and N6 atom of adenine residues as sites for covalent binding of metabolically activated 1-hydroxysafrole to mouse liver DNA in vivo. Cancer Res, 41: 2664–2671, 1981.
   PubMed Web of Science ®Google Scholar
• Osborne, M. R., Hardcastle, I. R., and Phillips, D. H., Minor products of reaction of DNA with a-acetoxytamoxifen. Carcinogenesis, 18: 539–543, 1997.
   PubMed Web of Science ®Google Scholar
• Rajaniemi, H., Rasanen, I., Koivisto, P., Peltonen, K., and Hemminki, K., Identification of the major tamoxifen-DNA adduct in rat liver by mass spectrometry. Carcinogenesis, 20: 305–309, 1999.
   PubMed Web of Science ®Google Scholar
• Shimada, T., Yamazaki, H., Mimura, M., Inui, Y., and Guengerich, F. P., Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. J Pharmacol Exp Therp, 270: 414–423, 1994.
   PubMed Web of Science ®Google Scholar
• Boocock, D. J., Maggs, J. L., Brown, K., White, I. N. H., and Park, B. K., Glucuronylation of alpha-hydroxytamoxifen: a deactivation pathway in humans? Br J Clin Pharmacol, 47: 578–579, 1999.
   Google Scholar