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

Abstract

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.

Potentiation of the mutagenicity and recombinagenicity of bleomycin in yeast by unconventional intercalating agents

“…Tamoxifen is nonmutagenic in standard bacterial assays [National Toxicology Program, 2005] but its metabolite a-hydroxytamoxifen was mutagenic in Salmonella strain TA1538-rHSTa and in a V79 cell hprt assay when a recombinant rat-liver hydroxysteroid sulfotransferase was expressed [Glatt et al, 1998]. Other studies showed tamoxifen to form DNA adducts and to be mutagenic, clastogenic and aneugenic in systems capable of its metabolic activation [Crofton-Sleigh et al, 1993;Styles et al, 1997;Glatt et al, 1998;White, 1999;Sargent et al, 1996;Styles et al, 2001;National Toxicology Program, 2005;Brown et al, 2007]. Tamoxifen is effective in the treatment and prevention of breast cancer, but it is a carcinogen for endometrial cancer [International Agency for Research on Cancer, 1996;White, 1999;National Toxicology Program, 2005;Brown et al, 2007;Grosse et al, 2009].…”

The formation and biological significance of N7-guanine adducts

“…Therefore, specific chemical syntheses are required to either obtain radioisotope-labeled test compounds or for chemical labeling of compounds of interest (postlabeling, derivatization). Unfortunately, access to AMS is limited worldwide (only 5 instruments as of 2007), mainly due to the expense of the mostly custom-made instruments [65]. …”

“Iron-saturated” bovine lactoferrin improves the chemotherapeutic effects of tamoxifen in the treatment of basal-like breast cancer in mice

“…Tamoxifen forms DNA adducts in human colon after administration, and may elevate the risk of gastrointestinal cancers [53]. It inhibits the growth of normal human colon epithelial cells [54].…”