Tamoxifen, an antiestrogen used in the endocrine therapy and chemoprevention of breast cancer, induces liver cancer in rodents and is associated with endometrial cancer in women. Estrogens also are implicated in the etiology of endometrial and breast cancer. The carcinogenicity of these agents may be mediated through their genotoxic effects. The goals of this research are to establish a mechanism for the genotoxicities of tamoxifen and estrogen and to find a safer alternative to tamoxifen. Oligodeoxynucleotides containing a single defined DNA adduct will be prepared by automated DNA synthesis. Using these site-specifically modified oligodeoxynucleotides, the mutagenic and repair potential of estrogen and anti-estrogen DNA adducts in mammalian cells will be determined. The three dimensional structure of tamoxifen- and estrogen adducts in DNA duplex also will be established, permitting us to understand the process of mutagenic and repair events which occur at lesion sites. Such modified oligodeoxynucleotides also will be employed as standards in ultrasensitive 32P-postlabeling and HPLC/electrochemical detector analyses designed to quantify DNA adducts and oxidatively damaged lesions in the tissues of rodents and monkeys treated with these drugs. Taken together, this information can be used to predict genotoxicity. Translational studies have been designed to detect adducts in the endometrial DNA of patients undergoing treatment with tamoxifen or toremifene. These experiments will provide biomarkers for molecular epidemiological studies and explore the relationship between tamoxifen therapy and the development of endometrial cancer in women treated with this drug. This research should lead to a safer alternative for women undergoing breast cancer therapy and for chemoprevention.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES009418-07
Application #
6790533
Study Section
Chemical Pathology Study Section (CPA)
Program Officer
Mcallister, Kimberly A
Project Start
1998-05-13
Project End
2007-07-31
Budget Start
2004-08-01
Budget End
2005-07-31
Support Year
7
Fiscal Year
2004
Total Cost
$338,625
Indirect Cost
Name
State University New York Stony Brook
Department
Pharmacology
Type
Schools of Medicine
DUNS #
804878247
City
Stony Brook
State
NY
Country
United States
Zip Code
11794
Suzuki, Naomi; Liu, Xiaoping; Laxmi, Y R Santosh et al. (2011) Anti-breast cancer potential of SS5020, a novel benzopyran antiestrogen. Int J Cancer 128:974-82
Laxmi, Y R Santosh; Liu, Xiaoping; Suzuki, Naomi et al. (2010) Anti-breast cancer potential of SS1020, a novel antiestrogen lacking estrogenic and genotoxic actions. Int J Cancer 127:1718-26
Poon, Kinning; Itoh, Shinji; Suzuki, Naomi et al. (2008) Miscoding properties of 6alpha- and 6beta-diastereoisomers of the N(2)-(estradiol-6-yl)-2'-deoxyguanosine DNA adduct by Y-family human DNA polymerases. Biochemistry 47:6695-701
Okamoto, Yoshinori; Liu, Xiaoping; Suzuki, Naomi et al. (2008) Increased antitumor potential of the raloxifene prodrug, raloxifene diphosphate. Int J Cancer 122:2142-7
Kim, Sung Yeon; Suzuki, Naomi; Laxmi, Y R Santosh et al. (2006) Inefficient repair of tamoxifen-DNA adducts in rats and mice. Drug Metab Dispos 34:311-7
Yasui, Manabu; Suzuki, Naomi; Laxmi, Y R Santosh et al. (2006) Translesion synthesis past tamoxifen-derived DNA adducts by human DNA polymerases eta and kappa. Biochemistry 45:12167-74
Hashiba, Masamichi; Kasahara, Toshihiko; Kim, Sung Yeon et al. (2006) DNA damage and altered gene expression of enzymes for metabolism and DNA repair by tamoxifen and toremifene in the female rat liver. Cancer Sci 97:468-77
Itoh, Shinji; Shibutani, Shinya; Ikegami, Masazumi et al. (2006) Synthesis of oligodeoxynucleotides containing a single 6alpha- or 6beta-diastereoisomer of N2-(estradiol-6-yl)-2'-deoxyguanosine. Chem Res Toxicol 19:450-6
Kim, Sung Yeon; Suzuki, Naomi; Laxmi, Y R Santosh et al. (2006) Antiestrogens and the formation of DNA damage in rats: a comparison. Chem Res Toxicol 19:852-8
Shibutani, Shinya; Kim, Sung Yeon; Suzuki, Naomi (2006) 32P-postlabeling DNA damage assays: PAGE, TLC, and HPLC. Methods Mol Biol 314:307-21

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