P106 A lack of evidence for the genotoxicity of tamoxifen and toremifene in the human endometrium

Carmichael, Paul L.; Neven, Patrick; Sardar, S.; Hoof, I. Van; Ugwumadu, Austin; Bourne, Tom; Tomás, Eija; Hellberg, Pår; Hewer, A; Davis, Warren; Phillips, David H.

doi:10.1016/s0959-8049(97)89323-9

Cited by 43 publications

(54 citation statements)

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“…There is, however, a reported increased risk of endometrial cancer in post-menopausal women (Fomander et al, 1993) not associated with any adducts in the endometrium (Carmichael et al, 1996) and indicating a non-genotoxic mechanism. At 20 mg day-' this increased risk of endometrial cancer is probably about two-to threefold (van Leeuwen et al, 1994), which is similar to the increased risk reported with unopposed oestrogen replacement therapy (ERT) associated with endometrial hyperplasia and atypia (Grady et al, 1995).…”

mentioning

confidence: 89%

The effects of norethisterone on endometrial abnormalities identified by transvaginal ultrasound screening of healthy post-menopausal women on tamoxifen or placebo

Powles

Bourne²,

Athanasiou³

et al. 1998

Br J Cancer

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Summary Tamoxifen (tam) is used extensively for treatment of patients with breast cancer and is being evaluated for chemoprevention in healthy women. It has, however, been reported to increase the risk of endometrial cancer in post-menopausal women, probably by an oestrogenic effect on the endometrium. It also causes endometrial cysts and polyps. The aims of this study were to identify the incidence of endometrial thickening, polyps and cysts by transvaginal ultrasound (TVUS) screening of a population of post-menopausal healthy women in the Royal Marsden tamoxifen chemoprevention trial and to evaluate the possible benefit from the use of intermittent norethisterone (NE) in women with persistent changes. Since 1990, we have undertaken regular TVUS, using an endovaginal B mode probe, of the 463 postmenopausal women in the trial randomized to tam (20 mg day-') or placebo (plac), without breaking the randomization code. Endometrial thickening (ET) was defined as .8 mm at the widest point across the myometrial cavity in the longitudinal plane, including any stromal changes. Cystic changes were defined as more than one hypoechogenic area > 1 mm. Polyps were identified using saline hydrosonography. Oral NE (2.5 mg day-1) was used for 21 days out of 28 for three consecutive cycles by women with persistent endometrium . 8 mm, including cystic and polypoid changes. TVUS was repeated after the three courses to evaluate any change caused by NE and endometrial biopsies, including hysteroscopy, was performed on those women with persistent abnormalities. A persistent ET . 8 mm was identified in 56 (24%) of the 235 women on tamoxifen compared with only 5 (2%) of 228 women on placebo (P <0.0005). Stromal changes, including cysts, were detected in 36 (15%) and polyps in 26 (11%) of the women on tamoxifen compared with only two (<1%) of the women on placebo (P << 0.0005). After 3 months of cyclical norethisterone, 39 of 47 women (83%) on tamoxifen had persistent ultrasound changes. However, 45 (96%) had a progesterone withdrawal bleed. Hysteroscopy was performed in 39 women on tamoxifen (28 endometrial biopsy, 15 polypectomy), five of whom had histological evidence of a proliferative endometrium and a further three had an atypical hyperplastic endometrium (one of whom had a focus of invasive carcinoma). The cysts and polyps which were detected in women on tam could not be reversed by NE and were presumably stromal and not of malignant risk. However, 96% of the women had withdrawal NE bleeding, indicating an oestrogenically primed endometrium which could be a mechanism for an increased risk of endometrial cancer. Further studies are required to ascertain whether a progestin would protect against this risk. As in other studies, these results indicate that any increased risk of endometrial cancer caused by tamoxifen is low, and that TVUS screening is probably not justified for asymptomatic women on tamoxifen. Group, 1992). Based on these findings, it is now widely used and many millions of women have had, or are now receiving, such ...

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confidence: 89%

The effects of norethisterone on endometrial abnormalities identified by transvaginal ultrasound screening of healthy post-menopausal women on tamoxifen or placebo

Powles

Bourne²,

Athanasiou³

et al. 1998

Br J Cancer

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“…However, in each case, adducts were only observed in samples from a fraction of the patients, indicating variability in tamoxifen metabolic activation, the formation or repair of DNA adducts. Other investigators have failed to detect adducts in human samples, applying similar methods and alternative high-performance liquid chromatography (HPLC)-electrospray ionization tandem mass spectrometry approaches (24,25). Part of the reason for these discrepancies is the fact that if damage is induced, it is likely to be close to or below the limits of detection achievable with the assays typically employed.…”

Section: Introductionmentioning

confidence: 99%

Tamoxifen Forms DNA Adducts in Human Colon after Administration of a Single [14C]-Labeled Therapeutic Dose

et al. 2007

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Tamoxifen is widely prescribed for the treatment of breast cancer and is also licensed in the United States for the prevention of this disease. However, tamoxifen therapy is associated with an increased occurrence of endometrial cancer in women, and there is also evidence that it may elevate the risk of colorectal cancer. The underlying mechanisms responsible for tamoxifen-induced carcinogenesis in women have not yet been elucidated, but much interest has focused on the role of DNA adduct formation. We investigated the propensity of tamoxifen to bind irreversibly to colorectal DNA when given to 10 women as a single [14 C]-labeled therapeutic (20 mg) dose, f18 h before undergoing colon resections. Using the sensitive technique of accelerator mass spectrometry, coupled with high-performance liquid chromatography separation of enzymatically digested DNA, a peak corresponding to authentic dG-N 2 -tamoxifen adduct was detected in samples from three patients, at levels ranging from 1 to 7 adducts/10 9 nucleotides. No [14 C]-radiolabel associated with tamoxifen or its major metabolites was detected. The presence of detectable CYP3A4 protein in all colon samples suggests that this tissue has the potential to activate tamoxifen to A-hydroxytamoxifen, in addition to that occurring in the systemic circulation, and direct interaction of this metabolite with DNA could account for the binding observed. Although the level of tamoxifeninduced damage displayed a degree of interindividual variability, when present, it was f10 to 100 times higher than that reported for other suspect human colon carcinogens such as 2-amino-1-methyl-6-phenyimidazo [4,5-b]pyridine. These findings provide a mechanistic basis through which tamoxifen could increase the incidence of colon cancers in women.

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“…Tamoxifen-DNA adducts (Philips et al 1994;Phillips 2001;Beland et al 1999;Gamboa da Costa et al 2001;Carthew et al 2001) can cause hepatic tumors. It has also been demonstrated that rat and human liver microsomal fractions metabolize tamoxifen to reactive intermediates that bind covalently protein and DNA (Mani and Kupfer 1991;Pathak and Bodell 1994;Carmichael et al 1996).…”

Section: Tamoxifenmentioning

confidence: 99%

“…A statistically significant chromosomal aberration and MN induced by tamoxifen revealed its clastogenic potency. Carmichael et al (1996) reported that tamoxifen did not cause DNA adducts in human endometrial cells. The authors concluded also that genotoxic events observed with tamoxifen in the rat may not apply to the human endometrium.…”

Section: Genotoxicitymentioning

confidence: 99%

Genotoxicity of the some selective estrogen receptor modulators: a review

2014

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The objective of this article is to review genotoxicological profile of the major selective estrogen receptor modulators, including clomiphene, tamoxifen, toremifene, raloxifene. These drugs have been used for infertility treatment and breast cancer prevention in high risk-women. However, some studies reported that especially tamoxifen is a genotoxic agent and is related with endometrial cancer. Our review indicate that clomiphene and tamoxifen were found as genotoxic agent in majority of the tests. However published reports showed that toremifene is a weakly genotoxic agent. The genotoxic effects of raloxifene are still poorly known. Further genotoxicity studies should be conducted especially for raloxifene.

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P106 A lack of evidence for the genotoxicity of tamoxifen and toremifene in the human endometrium

Cited by 43 publications

References 0 publications

The effects of norethisterone on endometrial abnormalities identified by transvaginal ultrasound screening of healthy post-menopausal women on tamoxifen or placebo

The effects of norethisterone on endometrial abnormalities identified by transvaginal ultrasound screening of healthy post-menopausal women on tamoxifen or placebo

Tamoxifen Forms DNA Adducts in Human Colon after Administration of a Single [14C]-Labeled Therapeutic Dose

Genotoxicity of the some selective estrogen receptor modulators: a review

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