Risk of endometrial cancer after tamoxifen treatment of breast cancer

Leeuwen, Flora E. van; Belt-Dusebout, Alexandra W. van den; Benraadt, J.; Diepenhorst, Fred W.; Tinteren, Harm van; Coebergh, Jan Willem; Kiemeney, Lambertus A.; Gimbrère, Charles H. F.; Otter, Renée; Schouten, Leo J.; Damhuis, Ronald A.; Bontenbal, M.

doi:10.1016/s0140-6736(94)92692-1

Cited by 527 publications

(196 citation statements)

References 23 publications

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“…As the risk of endometrial cancer associated with tamoxifen appears to be dose related (Rutqvist et al, 1987;van Leeuwen et al, 1994), with an excess being observed mostly at 40 mg day-' (Rutqvist et al, 1987), the maintenance of a significant modulation of tHcy at low dose supports the contention of a better risk-benefit ratio, a finding with potentially important implications for the outcome of the ongoing prevention trials.…”

Section: Discussionmentioning

confidence: 86%

Tamoxifen reduces plasma homocysteine levels in healthy women

Cattaneo

Baglietto²,

Zighetti³

et al. 1998

Br J Cancer

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Summary Treatment with tamoxifen is associated with reduced incidence of myocardial infarction. As plasma homocysteine is an independent risk factor for cardiovascular disease, we studied the effects of tamoxifen on plasma homocysteine in 66 healthy women participating in the Italian prevention trial of breast cancer who were randomized in a double-blind manner to tamoxifen 20 mg day-' or placebo for 5 years. They were aged between 35 and 70 years, had undergone previous hysterectomy for non-malignant conditions and had no cont(aindications to the use of tamoxifen. Plasma levels of total homocysteine (tHcy) were measured at randomization and after 2 and 6 months. The mean ± s.d. plasma levels of tHcy were 7.59 + 1.71 lmol 1-', 7.25 ± 1.61 and 7.09 + 1.33 in the tamoxifen group and 8.07 ± 2.06, 7.93 ± 1.77 and 8.12 + 2.04 in the placebo group at 0, 2 and 6 months (P= 0.008 for the between-group difference over time). The higher the baseline tHcy level, the greater was the lowering effect of tamoxifen. No statistically significant effect of age, body mass index or smoking habit on baseline tHcy levels and its variation over time was found. In conclusion, tamoxifen (20 mg day-' for 6 months) decreased plasma tHcy levels in healthy women. This effect may contribute to its protective effect on myocardial infarction.

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Section: Discussionmentioning

confidence: 86%

Tamoxifen reduces plasma homocysteine levels in healthy women

Cattaneo

Baglietto²,

Zighetti³

et al. 1998

Br J Cancer

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“…For those women using tamoxifen as adjuvant therapy for breast cancer, there is a substantial reduction in the rate of recurrence of breast cancer, but there is also a 3 to 6 times increase in the incidence of endometrial carcinoma [18][19][20][21] (Class 4). This risk is proportional both to the dose of the drug and the duration of therapy, with those women treated for 5 or more years experiencing a fourfold risk 36,37 (Class 4). Some evidence exists that, for women in whom endometrial carcinoma develops following prolonged tamoxifen use, both the grade and stage of the tumor may be higher, thereby potentially compromising survival 38 (Class 4).…”

Section: Endometrial Cancer and Tamoxifenmentioning

confidence: 99%

Investigation of Women with Postmenopausal Uterine Bleeding: Clinical Practice Recommendations

Munro

2014

TPJ

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“…However, reports have shown that tamoxifen can lead to an increased endometrial cancer risk (1)(2)(3)(4)(5)(6)(7)(8) and induce the formation of DNA adducts (9)(10)(11). One of the proposed bioactivation pathways leading to the toxicity of tamoxifen suggests that the generation of reactive intermediates such as the tamoxifen carbocation (12)(13)(14), o-quinone (15,16), and quinone methide (17)(18)(19) could cause DNA damage directly through the formation of DNA adducts or indirectly through the generation of reactive oxygen species, which oxidize DNA.…”

Section: Introductionmentioning

confidence: 99%

Oxidation of Raloxifene to Quinoids: Potential Toxic Pathways via a Diquinone Methide and o-Quinones

Liu

et al. 2004

Chem. Res. Toxicol.

134

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Raloxifene was approved in 1997 by the FDA for the treatment of osteoporosis in postmenopausal women, and it is currently in clinical trials for the chemoprevention of breast cancer. Before widespread use as a chemopreventive agent in healthy women, the potential cytotoxic mechanisms of raloxifene should be investigated. In the current study, raloxifene was incubated with GSH and either rat or human liver microsomes, and the metabolites and GSH conjugates were characterized using liquid chromatography-tandem mass spectrometry. Raloxifene was converted to raloxifene diquinone methide GSH conjugates, raloxifene o-quinone GSH conjugates, and raloxifene catechols. For comparison, three raloxifene catechols were synthesized and characterized. In particular, 7-hydroxyraloxifene was found to oxidize to the 6,7-o-quinone. As compared with raloxifene diquinone methide, which has a half-life of less than 1 s in phosphate buffer, the half-life of raloxifene 6,7-o-quinone was much longer at t 1/2 ) 69 ( 2.5 min. The stability offered by raloxifene 6,7-o-quinone implies that it may be more toxic than raloxifene diquinone methide. Cytotoxicity studies in the human breast cancer cell lines S30 and MDA-MB-231 showed that 7-hydroxyraloxifene was more toxic than raloxifene in both cell lines. These results suggest that raloxifene could be metabolized to electrophilic and redox active quinoids, which have the potential to cause toxicity in vivo.

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Risk of endometrial cancer after tamoxifen treatment of breast cancer

Cited by 527 publications

References 23 publications

Tamoxifen reduces plasma homocysteine levels in healthy women

Tamoxifen reduces plasma homocysteine levels in healthy women

Investigation of Women with Postmenopausal Uterine Bleeding: Clinical Practice Recommendations

Oxidation of Raloxifene to Quinoids: Potential Toxic Pathways via a Diquinone Methide and o-Quinones

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