Identification of tamoxifen–DNA adducts in the endometrium of women treated with tamoxifen

Shibutani, Shinya; Ravindernath, Anisetti; Suzuki, N.; Terashima, Isamu; Sugarman, Steven; Grollman, Arthur P.; Pearl, Michael L.

doi:10.1093/carcin/21.5.461

Cited by 79 publications

(115 citation statements)

References 27 publications

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“…The genotoxic theory is based on the fact that tamoxifen forms a DNA adduct, which has been detected in half of endometrial samples obtained from women treated with the drug. 37 This compound has been shown to induce mutations in simian cells; however, its significance in human endometrium is still unclear. 38 Another hypothesis is based on the estrogen receptor-dependent model.…”

Section: Discussionmentioning

confidence: 99%

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Clinicopathological and molecular analysis of endometrial carcinoma associated with tamoxifen

et al. 2008

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Use of tamoxifen for treatment and prevention of breast cancer is becoming increasingly common. Tamoxifen has been associated with increased risk of endometrial carcinoma, although the exact mechanism of action is unknown. The aim of our study was to seek a possible correlation between endometrial carcinoma, tamoxifen exposure and MSI, PTEN, b-catenin and K-ras abnormalities. A group of 18 patients with endometrial carcinoma following treatment with tamoxifen were selected. A control group included 15 patients with endometrial carcinoma and associated ovarian hyperthecosis and one patient with endometrial carcinoma and adult granulosa cell tumor of the ovary, chosen because both conditions are associated with increased production of estrogen and increased risk of endometrial carcinoma development. The second control group included 27 randomly selected consecutive patients with endometrial carcinoma without identifiable associated conditions. Immunostaining for b-catenin was performed on all cases; DNA was extracted and amplified by PCR with primers for b-catenin, K-ras and PTEN genes. BAT-25 and BAT-26 were analyzed to assess for MSI. There were 16 endometrioid endometrial carcinomas, one mixed carcinoma and one clear cell carcinoma among patients in the tamoxifen group. All patients with ovarian hyperthecosis and adult granulosa cell tumor had endometrioid endometrial carcinoma. In the random control group, there were 26 endometrioid endometrial carcinomas and one carcinosarcoma. Immunohistochemical and mutational analysis for b-catenin showed abnormalities in 4/11 (36%) and 3/10 (30%) informative cases in the tamoxifen group; 7/16 (44%) and 4/15 (27%) informative cases, respectively in the ovarian hyperthecosis group and 1/27 random control cases (4%) (Po0.05). Patients with tamoxifen exposure had more K-ras mutations and fewer PTEN mutations and MSI as opposed to controls, but the results were not statistically significant. In conclusion, there was a direct relationship between tamoxifen exposure and overexpression of b-catenin oncoprotein, which is known to play a major role in the pathogenesis of estrogen-driven, type I endometrial adenocarcinoma. Modern Pathology (2008) 21, 925-936; doi:10.1038/modpathol.2008 published online 23 May 2008 Keywords: endometrial carcinoma; pathogenesis; estrogen; tamoxifen; b-catenin Endometrial carcinoma is the most common malignancy of the female genital tract in the United States. It has been traditionally classified into two categories: type I tumors, estrogen driven and characterized by endometrioid morphology (70-80%) and type II tumors, which are unrelated to estrogen and show serous/clear cell differentiation.

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Section: Discussionmentioning

confidence: 99%

“…27,28 Another hypothesis stipulates a possible genotoxic effect of tamoxifen with formation of DNA adducts, but is still controversial. [29][30][31][32][33] The aim of our study was to analyze the expression of selected molecular markers in patients who developed endometrial carcinoma following tamoxifen exposure.…”

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Clinicopathological and molecular analysis of endometrial carcinoma associated with tamoxifen

et al. 2008

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“…The QM metabolites of TAMO (8) and some related drugs (9, 12, 14, 15 and 17) are known to react with both GSH and DNA through binding to the exocyclic N7 amino group of adenine [101][102][103][104][105]. However, some doubt remains regarding this, because some of these metabolites have been found to be extraordinarily stable, so that no adduct could be observed in vitro with DNA [105].…”

Section: Drugs With Qm Intermediates That Can React With Thiols and Nmentioning

confidence: 99%

Quinone Methides and their Prodrugs: A Subtle Equilibrium Between Cancer Promotion, Prevention, and Cure

Dufrasne¹,

Gelbcke²,

Nève³

et al. 2011

CMC

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Abstract:The importance of reactive drug metabolites in the pathogenesis of drug-induced toxicity has been investigated since the early 1950s, mainly to reveal the link between toxic metabolites and chemical carcinogenesis. This review mainly focuses on biologically active compounds, which generate reactive quinone methide (QM) intermediates either directly or after bioactivation. Several examples of anticancer drugs acting through the generation of QM electrophiles are given. The use of those drugs for chemotherapeutic purposes is also discussed. The key feature of those QM-generating drugs is their reactivity toward specific nucleophilic biological targets. Modulation of their reactivity represents a challenge for medicinal chemists because, depending on the reactivity of these QM intermediates, their interaction with critical proteins can alter the function of these key proteins and induce a wide variety of responses with functional consequences. Among the possible consequences, antiproliferative effects could be exploited for chemotherapeutic purposes. Information on how such QM-generating drugs can affect individual target proteins and their functional consequences are required to help the medicinal chemist in the design of more specific QM-generating molecules for chemotherapeutic use.

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“…On the other hand, TAM-DNA adducts are detected in a half of the endometrial samples obtained from TAM-treated women (Shibutani et al, 2000a). The site-specific dG-N 2 -TAM adducts display a high miscoding and mutagenic potential and primarily generate G to T transversions in mammalian cells (Terashima et al, 1999).…”

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K-ras mutation in the endometrium of tamoxifen-treated breast cancer patients, with a comparison of tamoxifen and toremifene

et al. 2005

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The putative presence of a mutation in codon 12 of the K-ras gene was investigated in the endometrium of tamoxifen (TAM) and toremifene (TOR)-treated breast cancer patients. DNA was extracted from fresh cytologic samples of the endometrium in 86 TAM and 21 TOR-treated breast cancer patients. Mutations were detected by enriched PCR and an enzyme-linked mini-sequence assay (ELMA). K-ras mutation was found in 35 TAM-treated endometrial samples, and in only one TOR-treated endometrium (Po0.003). In 24 premenopausal patients, K-ras mutation was found in seven (43.8%) of 16 patients with less than 47 months of TAM treatment, while none was found in eight patients with more than 48 months of TAM treatment (Po0.03). In 62 postmenopausal-amenorrheic patients, K-ras mutation was found in three (15.8%) of 19 patients with less than 23 months of TAM treatment, while it was found in 16 (61.5%) of 26 patients with 24 -47 months of TAM treatment and nine (52.9%) of 17 patients with more than 48 months of TAM treatment (P ¼ 0.002). The presence of K-ras mutation is significantly influenced by the duration of TAM treatment and menstrual status of the patients. TOR may have a lower potential genotoxicity than TAM.

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Identification of tamoxifen–DNA adducts in the endometrium of women treated with tamoxifen

Cited by 79 publications

References 27 publications

Clinicopathological and molecular analysis of endometrial carcinoma associated with tamoxifen

Clinicopathological and molecular analysis of endometrial carcinoma associated with tamoxifen

Quinone Methides and their Prodrugs: A Subtle Equilibrium Between Cancer Promotion, Prevention, and Cure

K-ras mutation in the endometrium of tamoxifen-treated breast cancer patients, with a comparison of tamoxifen and toremifene

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