Genotoxic effects of the novel mixed antiestrogen FC-1271a in comparison to tamoxifen and toremifene

  title={Genotoxic effects of the novel mixed antiestrogen FC-1271a in comparison to tamoxifen and toremifene},
  author={Utha Hellmann-Blumberg and Tracy L. Taras and Gregory T. Wurz and Michael W. DeGregorio},
  journal={Breast Cancer Research and Treatment},
Tamoxifen has been used for the treatment of breast cancer since the 1970s, but is considered a carcinogen because it has been linked to liver cancer in rats and an increased risk of endometrial cancer in patients. In rats, DNA adducts appear to be responsible for carcinogenesis, but their contribution to carcinogenesis in humans is not clear. FC-1271a and toremifene are mixed antiestrogens similar to tamoxifen. In order to compare the genotoxicity of these different triphenylethylenes, we… 

Ospemifene inhibits the growth of dimethylbenzanthracene-induced mammary tumors in Sencar mice

Formation of tamoxifen-DNA adducts in multiple organs of adult female cynomolgus monkeys dosed with tamoxifen for 30 days.

It is indicated that cynomolgus monkeys are capable of metabolizing TAM to genotoxic intermediates that form TAM-DNA adducts in multiple tissues, as well as on-line sample preparation and high-performance liquid chromatography (HPLC).

Ospemifene and 4-hydroxyospemifene effectively prevent and treat breast cancer in the MTag.Tg transgenic mouse model

Ospemifene does not seem to pose a breast cancer risk in animals and slows down cancer development and progression in the MTag.Tg model, and does not exert an estrogenic effect in the breast tissue at doses equivalent to human dosing.

Effect of Coenzyme Q10, Riboflavin and Niacin on Tamoxifen treated postmenopausal breast cancer women with special reference to blood chemistry profiles

TAM on co-administration with CoRN has a favorable impact on various blood chemistry profiles, however, large scale randomized studies over a longer time span are required to ascertain the safety and efficacy of co- Administrating antioxidants with conventional chemotherapy.

The effects of selective oestrogen receptor modulators in the uterus

It is concluded that not all oestrogens agonists are the same in this model and while oestrogenicity is needed for the development of adenomyosis additional, unidentified factors, are required.

Metabolites of Tamoxifen as the Basis of Drug Development

Tamoxifen is a prodrug but it is the metabolite 4-hydroxy-N-desmethyltam Oxifen or endoxifens that has attracted pharmacogenetic interest.

The effect of dimethyl dimethoxy biphenyl dicarboxylate (DDB) against tamoxifen-induced liver injury in rats: DDB use is curative or protective.

The oral administration of DDB in a dose of 200 mg/kg body weight daily for 10 successive days resulted in alleviation of the oxidative stress status of tamoxifen-intoxicated liver injury in rats as observed by significant increments in the antioxidant enzymes.

Estrogen receptors as therapeutic targets in breast cancer.

The development of resistance to endocrine therapy remains a clinically important problem, and laboratory models based on human breast cancer cells grown as tumors in immune-compromised mice have led to important insights into this problem.

Effects of ospemifene, a novel selective estrogen-receptor modulator, on human breast tissue ex vivo

Osp inhibited proliferation and opposed E2 stimulation in normal HBT in an efficacious, but less potent way than Ral and Tam, and the ESR1 PvuII polymorphisms may influence the responsiveness of HBT to E2 and SERMs.



Effects of chronic administration of tamoxifen and toremifene on DNA adducts in rat liver, kidney, and uterus.

The effectiveness of TOR and TAM in increasing endogenous DNA adducts indicates that a mechanism other than direct DNA damage may also be involved in their carcinogenicity.

Tamoxifen and toremifene in breast cancer: comparison of safety and efficacy.

  • A. BuzdarG. Hortobagyi
  • Medicine, Biology
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology
  • 1998
Toremifene is not likely to be used as second-line therapy after tamoxifen failure due to cross-resistance, and its ultimate place in therapy of advanced breast cancer remains to be determined.

Strong intensification of mouse hepatic tamoxifen DNA adduct formation by pretreatment with the sulfotransferase inhibitor and ubiquitous environmental pollutant pentachlorophenol.

It was apparent that there are two pathways of metabolic activation of tamoxifen, one being sensitive and the other resistant to pentachlorophenol, and that the mechanism of this effect may involve the inhibition of sulfation of a tamoxIFen metabolite involved in the detoxication of the drug to nonelectrophilic derivatives.

Genotoxic potential of tamoxifen and analogues in female Fischer F344/n rats, DBA/2 and C57BL/6 mice and in human MCL-5 cells.

Tamoxifen induced a significant increase in micronucleus formation in a dose dependent manner in cultures of MCL-5 cells, a human cell line that expresses 5 different human cytochrome P450 isoenzymes, as well as epoxide hydrolase.

Investigation of the formation and accumulation of liver DNA adducts in mice chronically exposed to tamoxifen.

The results suggest that, in contrast to the rat, tamoxifen is non-carcinogenic in mice because it does not cause sufficient cumulative DNA damage, or act as a promoter by causing cell proliferation.

Identification of tamoxifen-DNA adducts formed by 4-hydroxytamoxifen quinone methide.

It is shown that 4-hydroxytamoxifen quinone methide reacts with DNA to form covalent adducts, which are characterized as (E)- and (Z)-alpha-(deoxyguanosin-N2-yl)-4-hydroxifen.

Selective Estrogenic Effects of a Novel Triphenylethylene Compound, FC1271a, on Bone, Cholesterol Level, and Reproductive Tissues in Intact and Ovariectomized Rats1.

The bone-sparing, antitumor, and cholesterol-lowering effects of FC1271a combined with a low uterotropic activity and lack of liver toxicity indicate that FC 1271a could be an important alternative in planning antiosteoporosis therapy for estrogen deficiency.

Activation of tamoxifen and its metabolite alpha-hydroxytamoxifen to DNA-binding products: comparisons between human, rat and mouse hepatocytes.

The metabolic activation of tamoxifen and its metabolite alpha-hydroxytamoxifen in primary cultures of rat, mouse and human hepatocytes has been compared. The extent of formation of DNA adducts in

Selective estrogenic effects of a novel triphenylethylene compound, FC1271a, on bone, cholesterol level, and reproductive tissues in intact and ovariectomized rats.

The bone-sparing, antitumor, and cholesterol-lowering effects of FC1271a combined with a low uterotropic activity and lack of liver toxicity indicate that FC 1271a could be an important alternative in planning antiosteoporosis therapy for estrogen deficiency.

Tamoxifen: evidence by 32P-postlabeling and use of metabolic inhibitors for two distinct pathways leading to mouse hepatic DNA adduct formation and identification of 4-hydroxytamoxifen as a proximate metabolite.

The results presented herein demonstrate conclusively that TAM was activated to DNA-reactive compounds along two distinct pathways which contrasted in their responses to metabolic inhibitors.