Antiestrogens and the Formation of DNA Damage in Rats:  A Comparison

Kim, Sung Yeon; Suzuki, N.; Laxmi, Y. R. Santosh; Umemoto, Atsushi; Matsuda, Tomonari; Shibutani, Shinya

doi:10.1021/tx060052n

Cited by 13 publications

(14 citation statements)

References 42 publications

(69 reference statements)

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“…S3B). Because 4-hydroxytamoxifen itself is known not to result in DNA damage (27), and no ERK1/2 phosphorylation was detected in the vector control cell line, these data strongly suggest that signaling originated from DRAF-ER* and not from 4-hydroxytamoxifen (Supplementary Fig. S3B ).…”

Section: Resultsmentioning

confidence: 86%

Extracellular Signal-Related Kinase Positively Regulates Ataxia Telangiectasia Mutated, Homologous Recombination Repair, and the DNA Damage Response

et al. 2007

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The accurate joining of DNA double-strand breaks by homologous recombination repair (HRR) is critical to the long-term survival of the cell. The three major mitogenactivated protein (MAP) kinase (MAPK) signaling pathways, extracellular signal-regulated kinase (ERK), p38, and c-Jun-NH 2 -kinase (JNK), regulate cell growth, survival, and apoptosis. To determine the role of MAPK signaling in HRR, we used a human in vivo I-SceI-based repair system. First, we verified that this repair platform is amenable to pharmacologic manipulation and show that the ataxia telangiectasia mutated (ATM) kinase is critical for HRR. The ATM-specific inhibitor KU-55933 compromised HRR up to 90% in growth-arrested cells, whereas this effect was less pronounced in cycling cells. Then, using well-characterized MAPK small-molecule inhibitors, we show that ERK1/2 and JNK signaling are important positive regulators of HRR in growth-arrested cells. On the other hand, inhibition of the p38 MAPK pathway generated an almost 2-fold stimulation of HRR. When ERK1/2 signaling was stimulated by oncogenic RAF-1, an f2-fold increase in HRR was observed. KU-55933 partly blocked radiation-induced ERK1/2 phosphorylation, suggesting that ATM regulates ERK1/2 signaling. Furthermore, inhibition of MAP/ERK kinase (MEK)/ERK signaling resulted in severely reduced levels of phosphorylated (S1981) ATM foci but not ;-H2AX foci, and suppressed ATM phosphorylation levels >85% throughout the cell cycle. Collectively, these results show that MAPK signaling positively and negatively regulates HRR in human cells. More specifically, ATM-dependent signaling through the RAF/MEK/ ERK pathway is critical for efficient HRR and for radiationinduced ATM activation, suggestive of a regulatory feedback loop between ERK and ATM. [Cancer Res 2007;67(3):1046-53]

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Section: Resultsmentioning

confidence: 86%

Extracellular Signal-Related Kinase Positively Regulates Ataxia Telangiectasia Mutated, Homologous Recombination Repair, and the DNA Damage Response

et al. 2007

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“…In vivo, it is excreted in the bile by export pumps and forms adducts with proteins in the bile canalicular domain of the plasma membrane [247] [250]. Here, we examine another facet of tamoxifen bioactivity, namely its genotoxicity as evidenced by an increased incidence of endometrial cancer in treated patients [252] [253]. The acyl glucuronide is of further interest due to its oxidative metabolism to 4'-hydroxydiclofenac acyl glucuronide (not shown); the toxicological significance of this metabolite does not appear to be well-documented.…”

Section: Fig 548mentioning

confidence: 99%

ChemInform Abstract: The Biochemistry of Drug Metabolism — An Introduction. Part 5. Metabolism and Bioactivity

Testa

Kraemer

2009

ChemInform

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The Part 5 of our biochemical introduction to drug metabolism presents the pharmacological and toxicological consequences of drug and xenobiotic metabolism. As we have already shown [1 -5] and discuss here with specific focus, the consequences of the biotransformation of foreign compounds explain to a large extent the immense significance this discipline has acquired. When it comes to drug metabolism, its consequences are of utmost relevance in fields such as drug discovery and development, clinical pharmacology and toxicology, and therapeutics. The same relevance is now recognized to xenobiotic metabolism in, e.g., agrochemistry and food chemistry, industrial hygiene, workplace safety, and environmental welfare.Presenting the pharmacological and toxicological consequences of drug and xenobiotic metabolism can be achieved by focusing on rules and general principles, with a high risk of remaining abstract and failing to impress readers. Or it can be done with examples only, with the consequence that readers will remember fragmental data which may not help them to generalize and reason by analogy. The didactic approach followed here is simply the middle course, whereby we start with principles and illustrate them with examples, while, at other occasions, discussing illustrative cases from which principles are then derived.

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“…Unlike TAM, TOR does not cause hepatocarcinoma in rats,26 although the metabolic fate of TOR is similar to that of TAM. In fact, no DNA adducts were detected in the livers of rats treated with TOR 8, 26, 27. This may be due to steric hindrance caused by the bulky chlorine atom positioned at the ethyl moiety of TOR (Fig.…”

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confidence: 95%

Anti‐breast cancer potential of SS1020, a novel antiestrogen lacking estrogenic and genotoxic actions

Laxmi

Suzuki

et al. 2010

Intl Journal of Cancer

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Long-term treatment with tamoxifen (TAM) increases the risk of developing endometrial cancer in women. Several antiestrogens developed in last decades have been discontinued from clinical testing because of their undesirable effects on the uterus. To avoid such serious side-effect while increasing the drug's anti-breast cancer potential, new triphenylethylene antiestrogens, 2E-3-{4-[(E)-4-chloro-1-(4-hydroxyphenyl)-2-phenylbut-1-enyl]-phenyl} acrylic acid (SS1020) and 2E-3-{4-[(Z)-4-chloro-1,2-diphenylbut-1-enyl]phenyl}acrylic acid (SS1010), were designed as safer alternatives. Unlike TAM, SS1020 does not present significant uterotrophic potential in rats; in contrast, SS1010, a compound removing a 4-OH moiety from SS1020, represented weak uterotrophic activity. The structurally related compounds 4-hydroxytamoxifen, toremifene, ospemifene, raloxifene (RAL) and GW5638 all have uterotrophic activity. In addition, SS1020 and SS1010 exhibit no genotoxic activity to damage hepatic DNA in rats. Therefore, SS1020 was selected as a safer antiestrogen candidate and used for evaluating the antitumor potential in animals. At the human equivalent doses of TAM, SS1020 had antitumor potential much higher than that of TAM, RAL and GW5638 against 7,12-dimethylbenz(a)anthracene-induced mammary carcinoma in rats. The growth of human MCF-7 breast cancer xenograft implanted into athymic nude mice was also effectively suppressed by SS1020. SS1020, lacking estrogenic and genotoxic actions and having strong antitumor potency superior to that of TAM and RAL, could be a safer alternative for breast cancer therapy and prevention.Tamoxifen (TAM; the structure is given in Fig. 1a) is widely used as a first-line endocrine therapy for breast cancer patients with positive estrogen receptors (ER) 1 and as a prophylactic agent for women at high risk of developing this disease. 2 Besides the significant benefit, long-term administration of TAM has serious adverse effects, including endometrial cancer in women. [2][3][4] The carcinogenic effect is thought to involve initiation and/or promotion due to TAM-induced DNA damage as well as the drug's estrogenic action (reviewed in Refs. 5, 6). TAM and its metabolites are a-hydroxylated and undergo Osulfonation catalyzed by hydroxysteroid sulfotransferase, after which they react with guanine residues in cellular DNA, forming TAM-DNA adducts. 5 TAM-DNA adducts were detected in the liver of rodents treated with TAM, 7,8 in several tissues, including the ovary and uterus of monkeys, 9 and in the endometrium of certain women receiving TAM. 10,11 K-ras mutations were detected frequently in the endometria of women treated with TAM. 12 Because TAM-DNA adducts are highly mutagenic 13 and not rapidly repaired, 14 the DNA adducts may contribute to the initiation of endometrial cancer. Like estrogens, TAM is a partial ER agonist in uterine tissue 15 ; such estrogenic effects may also contribute to promoting endometrial cancer. 16 Therefore, TAM alternatives free of genotoxic and estrogenic potential are required t...

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Antiestrogens and the Formation of DNA Damage in Rats: A Comparison

Cited by 13 publications

References 42 publications

Extracellular Signal-Related Kinase Positively Regulates Ataxia Telangiectasia Mutated, Homologous Recombination Repair, and the DNA Damage Response

Extracellular Signal-Related Kinase Positively Regulates Ataxia Telangiectasia Mutated, Homologous Recombination Repair, and the DNA Damage Response

ChemInform Abstract: The Biochemistry of Drug Metabolism — An Introduction. Part 5. Metabolism and Bioactivity

Anti‐breast cancer potential of SS1020, a novel antiestrogen lacking estrogenic and genotoxic actions

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