Identification of tamoxifen-DNA adducts in the endometrium of women treated with tamoxifen.
The risk of developing endometrial cancer increases significantly for women treated with tamoxifen (TAM); the present study was designed to investigate the mechanism of this carcinogenic effect. Endometrial tissue was obtained from 16 women treated for varying lengths of time with TAM and from 15 untreated control subjects. DNA was analyzed with a (32)P-post-labeling/HPLC on-line monitoring assay capable of detecting 2.5 adducts/10(10) nucleotides. Using this sensitive and specific assay, TAM-DNA adducts were detected in eight women. The major adducts found were trans and cis epimers of alpha-(N(2)-deoxyguanosinyl) tamoxifen (dG-N(2)-TAM); levels ranged between 0.2-12 and 1.6-8.3 adducts/10(8) nucleotides, respectively. There was marked inter-individual variation in the relative amounts of cis and trans adducts present. Low levels (0.74-1.1 adducts/10(8) nucleotides) of trans and cis forms of dG-N(2)-TAM N-oxide were detected in one patient. DNA adducts derived from 4-hydroxytamoxifen quinone methide were not observed. We conclude from this analysis that trans and cis dG-N(2)-TAMs accumulate in significant amounts in the endometrium of many, but not all, women treated with this drug. The level of adducts found, coupled with the previous demonstration of their mutagenicity [Cancer Res., 59, 2091, 1999], suggest that a genotoxic mechanism may be responsible for TAM-induced endometrial cancer.
Laboratory of Chemical Biology, Department of Pharmacological Sciences, Division of Oncology and Division of Obstetrics and Gynecology, School of Medicine, State University of New York at Stony Brook, Stony Brook, NY 11794, USA. shinya@pharm.sunysb.edu
S
S
Shibutani
A
A
Ravindernath
N
N
Suzuki
I
I
Terashima
S M
SM
Sugarman
A P
AP
Grollman
M L
ML
Pearl
D000328:Adult; D000368:Aged; D002273:Carcinogens / Q000009:adverse effects / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D018736:DNA Adducts / Q000032:analysis*; D004717:Endometrium / Q000378:metabolism*; D004965:Estrogen Antagonists / Q000009:adverse effects / Q000378:metabolism* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008875:Middle Aged; D010761:Phosphorus Radioisotopes; D012680:Sensitivity and Specificity; D013237:Stereoisomerism; D013629:Tamoxifen / Q000009:adverse effects / Q000031:analogs & derivatives / Q000032:analysis / Q000378:metabolism* / Q000627:therapeutic use
D002273:Carcinogens; D018736:DNA Adducts; D004965:Estrogen Antagonists; D010761:Phosphorus Radioisotopes; C105083:alpha-(N(2)-deoxyguanosinyl)tamoxifen; D013629:Tamoxifen; D004247:DNA