Journal article
Mechanism of lower genotoxicity of toremifene compared with tamoxifen
Cancer research (Chicago, Ill.), Vol.61(10), pp.3925-3931
2001
PMID: 11358807
Abstract
An increased incidence of endometrial cancer has been reported in breast cancer patients taking tamoxifen (TAM) and in healthy women participating in the TAM chemoprevention trials. Because TAM-DNA adducts are mutagenic and detected in the endometrium of women treated with TAM, TAM adducts are suspected to initiate the development of endometrial cancer. Treatment with TAM has been known to promote hepatocarcinoma in rats, but toremifene (TOR), a chlorinated TAM analogue, did not. TAM adducts are primarily formed via sulfonation of the alpha-hydroxylated TAM metabolites. To explore the mechanism of the lower genotoxicity of TOR, the formation of DNA adducts induced by TOR metabolites was measured using (32)P-postlabeling/ high-performance liquid chromatography analysis and compared with that of TAM metabolites. When alpha-hydroxytoremifene was incubated with DNA, 3'-phosphoadenosine 5'-phosphosulfate, and either rat or human hydroxysteroid sulfotransferase, the formation of DNA adducts was two orders of magnitude lower than that of alpha-hydroxytamoxifen. alpha-hydroxytoremifene was a poor substrate for rat and human hydroxysteroid sulfotransferases. In addition, the reactivity of alpha-acetoxytoremifene, a model activated form of TOR, with DNA was much lower than that of alpha-acetoxytamoxifen. Thus, TOR is likely to have lower genotoxicity than TAM. TOR may be a safer alternative by avoiding the development of endometrial cancer.
Details
- Title: Subtitle
- Mechanism of lower genotoxicity of toremifene compared with tamoxifen
- Creators
- Shinya Shibutani - Laboratory of Chemical Biology, Department of Pharmacological Sciences, State University of New York at Stony Brook, Stony Brook, New York 11794-8651, United StatesAnisetti Ravindernath - Laboratory of Chemical Biology, Department of Pharmacological Sciences, State University of New York at Stony Brook, Stony Brook, New York 11794-8651, United StatesIsamu Terashima - Laboratory of Chemical Biology, Department of Pharmacological Sciences, State University of New York at Stony Brook, Stony Brook, New York 11794-8651, United StatesNaomi Suzuki - Laboratory of Chemical Biology, Department of Pharmacological Sciences, State University of New York at Stony Brook, Stony Brook, New York 11794-8651, United StatesY. R Laxmi - Laboratory of Chemical Biology, Department of Pharmacological Sciences, State University of New York at Stony Brook, Stony Brook, New York 11794-8651, United StatesYoshikazu Kanno - Pharmaceuticals Group, Nippon Kayaku Co. Ltd., Tokyo 115-8588, JapanMasanobu Suzuki - Pharmaceuticals Group, Nippon Kayaku Co. Ltd., Tokyo 115-8588, JapanT. Idil Apak - Division of Medicinal and Natural Products Chemistry, College of Pharmacy, University of Iowa, Iowa City, Iowa 52242, United StatesJonathan J Sheng - Division of Medicinal and Natural Products Chemistry, College of Pharmacy, University of Iowa, Iowa City, Iowa 52242, United StatesMichael W Duffel - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Cancer research (Chicago, Ill.), Vol.61(10), pp.3925-3931
- Publisher
- American Association for Cancer Research
- PMID
- 11358807
- ISSN
- 0008-5472
- eISSN
- 1538-7445
- Language
- English
- Date published
- 2001
- Academic Unit
- Molecular Physiology and Biophysics; Pharmaceutical Sciences and Experimental Therapeutics; Medicinal and Natural Products Chemistry
- Record Identifier
- 9984303285802771
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