Diethylstilbestrol liver carcinogenicity and modification of DNA in rats

Williams, Gary M.; Iatropoulos, Michael J.; Cheung, Raymond; Radi, L.; Wang, C.X.

doi:10.1016/0304-3835(93)90146-z

Cited by 27 publications

(10 citation statements)

References 13 publications

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“…The expected time from tumour initiation to clinically detectable cancer has been considered to be between 10 and 15 years. The mechanism of TAM-induced carcinogenicity may be partly hormonal (Metzler and Degen, 1987;Williams et al, 1993), i.e. promotion of existing tumours, and partly nonhormonal, i.e.…”

Section: Discussionmentioning

confidence: 99%

Comparison of toremifene and tamoxifen in post-menopausal patients with advanced breast cancer: a randomized double-blind, the 'nordic' phase III study

Pyrhönen

Valavaara²,

Modig³

et al. 1997

Br J Cancer

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SummaryThe study was planned to compare, in a prospective double-blind randomized trial, the efficacy and safety of toremifene (TOR) and tamoxifen (TAM) in post-menopausal patients with advanced breast cancer who have not had prior systemic therapy for advanced disease. Four hundred and fifteen post-menopausal patients with oestrogen receptor (ER)-positive or ER-unknown advanced breast cancer were randomly assigned to receive daily either 60 mg TOR or 40 mg TAM. The patients were stratified to measurable and non-measurable but evaluable groups. They were assessed for response to therapy, time to progression (TTP), time to treatment failure (TTF), response duration, overall survival and drug toxicity. Two hundred and fourteen patients were randomized into TOR and 201 into TAM treatment. The response rate (complete + partial) was 31.3% for TOR and 37.3% for TAM (P = 0.215). The 95% confidence interval (Cl) for the 6% difference was -15.1% to 3.1%. The median TTP was 7.3 months for TOR and 10.2 months for TAM (P = 0.047). The 95% Cl for the hazard ratio of 0.80 was 0.64-1.00. A percentage of the TOR patients (9.8%) and the TAM patients (18.9%) discontinued the treatment prematurely (P = 0.011) for various reasons. Consequently, the median TTF of 6.3 vs 8.5 months did not differ significantly (P = 0.271). The hazard ratio was 0.89 and the subsequent 95% Cl 0.73-1.09. The median overall survival was 33.0 months for TOR and 38.7 months for TAM (P = 0.645). The hazard ratio was 0.94 with 95% Cl of 0.73-1.22. The transient difference in TTP may be related to an imbalance in ER content of the tumours. When only patients with ER-positive tumours were considered (n = 238), no difference between two treatments was seen (P = 0.578). TAM was associated with an overall slightly higher frequency of adverse drug reactions than TOR (44.3 vs 39.3%) and a higher discontinuation rate due to these events (3.5% vs 0.9%). Treatment-emerged moderate dizziness (P = 0.026) and cataracts (P = 0.026) were more frequent among TAM than among TOR patients. In conclusion, TOR (60 mg day1) and TAM (40 mg day-1) are equally effective and safe in the treatment of advanced post-menopausal ER-positive or ER-unknown breast cancer.Keywords: antioestrogen; post-menopausal women; advanced breast cancer Tamoxifen (TAM) is the most common alternative for initial endocrine therapy of patients with recurrent or metastatic breast cancer. The overall response rate of post-menopausal women to TAM varies from 20% to 60% (Jaiyesimi et al, 1995). This wide range is largely due to the variability of prognostic factors in different study populations and to heterogeneous quality assessment. TAM, when given as an adjuvant treatment, is associated with a 20% mortality reduction (Santen et al, 1990; Early Breast Cancer Trialists' Collaborative Group, 1992).The presence of oestrogen receptors (ERs) in the breast cancer cells is the most important factor associated with successful treatment with TAM. Approximately 70% of al primary breast cancers

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Section: Discussionmentioning

confidence: 99%

Comparison of toremifene and tamoxifen in post-menopausal patients with advanced breast cancer: a randomized double-blind, the 'nordic' phase III study

Pyrhönen

Valavaara²,

Modig³

et al. 1997

Br J Cancer

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“…related carcinogenesis, as seen with diethylstilbestrol (DES) induced uterine tumors in transgenic MT-mER mice(Couse et al, 1997), which greatly overexpress ER-α(Dickson and Stancel, 2000). Because estrogens are also linked to HCC(Williams et al, 1993; NTP, 2004b;2004c), we assessed expression of ER-α and estrogen-regulated/linked genes in normal liver specimens from C3H adult male mice bearing in utero arsenic-induced HCC(Waalkes et al, 2004b) from our tumor end-point study(Waalkes et al, 2003). A marked overexpression of hepatic ER-α at the transcript and protein level occurred in adult males bearing HCC induced by in utero arsenic(Waalkes et al, 2004b).…”

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confidence: 99%

Transplacental arsenic carcinogenesis in mice

Waalkes

Liu

Diwan

2007

Toxicology and Applied Pharmacology

164

149

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Our work has focused on the carcinogenic effects of in utero arsenic exposure in mice. Our data show that a short period of maternal exposure to inorganic arsenic in the drinking water is an effective, multi-tissue carcinogen in the adult offspring. These studies have been reproduced in three temporally separate studies using two different mouse strains. In these studies pregnant mice were treated with drinking water containing sodium arsenite at up to 85 ppm arsenic from days 8 to 18 of gestation, and the offspring were observed for up to 2 years. The doses used in all these studies were well tolerated by both the dam and offspring. In C3H mice, two separate studies show male offspring exposed to arsenic in utero developed liver carcinoma and adrenal cortical adenoma in a dose-related fashion during adulthood. Prenatally exposed female C3H offspring show dose-related increases in ovarian tumors and lung carcinoma and in proliferative lesions (tumors plus preneoplastic hyperplasia) of the uterus and oviduct. In addition, prenatal arsenic plus postnatal exposure to the tumor promoter, 12-O-tetradecanoyl phorbol-13-acetate (TPA) in C3H mice produces excess lung tumors in both sexes and liver tumors in females. Male CD1 mice treated with arsenic in utero develop tumors of the liver and adrenal and renal hyperplasia while females develop tumors of urogenital system, ovary, uterus and adrenal and hyperplasia of the oviduct. Additional postnatal treatment with diethylstilbestrol or tamoxifen after prenatal arsenic in CD1 mice induces urinary bladder transitional cell proliferative lesions, including carcinoma and papilloma, and enhances the carcinogenic response in the liver of both sexes. Overall this model has provided convincing evidence that arsenic is a transplacental carcinogen in mice with the ability to target tissues of potential human relevance, such as the urinary bladder, lung and liver. Transplacental carcinogenesis clearly occurs with other agents in humans and investigating a potential transplacental component of the human carcinogenic response to arsenic should be a research priority.

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“…Concerning nonhormonal properties of the test chemicals (most of which have only be defined in vitro ), GEN inhibits a range of enzymes, including tyrosine kinases (Akiyama et al 1987), nitric oxide synthase (Duarte et al 1997), and topoisomerase II (Okura et al 1988), and also decreases calcium-channel activity (Potier and Rovira 1999), lipid peroxidation (Arora et al 1998), and diacylglycerol synthesis (Dean et al 1989). Likewise, DES is reported to induce aneuploidy in mammalian cells (Aardema et al 1998) and to bind to rat liver DNA (Williams et al 1993). More recently, some phytoestrogens were reported to inhibit the aromatase-mediated conversion of testosterone to E 2 in vitro (Almstrup et al 2002), and equol, the major circulating estrogenic metabolite associated with the dietary ingestion of phytoestrogens, is reported to selectively sequester dihydrotestosterone and thereby to act as a functional antiandrogen in vivo (Lund et al 2004).…”

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confidence: 99%

The Need to Decide If All Estrogens Are Intrinsically Similar

Moggs¹,

Ashby²,

Tinwell³

et al. 2004

Environ Health Perspect

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We used gene expression profiling to investigate whether the molecular effects induced by estrogens of different provenance are intrinsically similar. In this article we show that the physiologic estrogen 17β-estradiol, the phytoestrogen genistein, and the synthetic estrogen diethylstilbestrol alter the expression of the same 179 genes in the intact immature mouse uterus under conditions where each chemical has produced an equivalent gravimetric and histologic uterotrophic effect, using the standard 3-day assay protocol. Data are also presented indicating the limitations associated with comparison of gene expression profiles for different chemicals at times before the uterotrophic effects are fully realized. We conclude that the case has yet to be made for regarding synthetic estrogens as presenting a unique human hazard compared with phytoestrogens and physiologic estrogens.

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Diethylstilbestrol liver carcinogenicity and modification of DNA in rats

Cited by 27 publications

References 13 publications

Comparison of toremifene and tamoxifen in post-menopausal patients with advanced breast cancer: a randomized double-blind, the 'nordic' phase III study

Comparison of toremifene and tamoxifen in post-menopausal patients with advanced breast cancer: a randomized double-blind, the 'nordic' phase III study

Transplacental arsenic carcinogenesis in mice

The Need to Decide If All Estrogens Are Intrinsically Similar

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