ABSTRACT
Tamoxifen (TAM) causes cancer in rat liver and human endometrium, whereas the carcinogenicity of its chlorinated analogue toremifene (TOR) has not been observed. To elucidate the genotoxicity of TOR, the capability of forming DNA adducts by TOR was examined in the leukocytes of patients treated with TOR. Leukocytes were collected from 27 breast cancer patients (57.7 +/- 11.4 years old) taking TOR (40 mg/day for 25 patients, 80 mg/day for one patient, and 120 mg/day for one patient; average duration, approximately 12 months) and 20 untreated breast cancer patients (58.2 +/- 12.3 years old). The DNA extracted was analyzed by (32)P-postlabeling/high-performance liquid chromatography. No DNA adducts were detected in the leukocytes of either TOR-treated or nontreated patients. Our results contrast to the previous observation detecting TAM-DNA adducts in several patients treated with TAM, indicating that TOR is less genotoxic to humans.
Subject(s)
Antineoplastic Agents, Hormonal/toxicity , Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , DNA Adducts/analysis , Leukocytes/chemistry , Toremifene/toxicity , Adult , Aged , Aged, 80 and over , Antineoplastic Agents, Hormonal/therapeutic use , Chromatography, High Pressure Liquid , DNA, Neoplasm/chemistry , DNA, Neoplasm/drug effects , DNA, Neoplasm/isolation & purification , Female , Humans , Middle Aged , Toremifene/therapeutic useABSTRACT
Tamoxifen (TAM), a widely used antiestrogen for breast cancer therapy and chemoprevention, increases the incidence of endometrial cancer in women. The formation of DNA adducts induced by tamoxifen may initiate endometrial cancer. To evaluate the genotoxic risk of TAM, the formation of DNA adducts in leukocytes was examined. Blood samples were collected from 47 breast cancer patients (61.7 +/- 12.5 years) taking TAM (20 mg/day; average duration until sampling, approximately 37 months) and 20 untreated patients (58.2 +/- 12.3 years), and their leukocyte DNA was analyzed by 32P-postlabeling/HPLC analysis. This assay resolves synthetic standards, trans- and cis-diastereoisomers of alpha-(N2-deoxyguanosinyl)tamoxifen 3'-monophosphate (dG3'P-N2-TAM), alpha-(N2-deoxyguanosinyl)-N-desmethyltamoxifen 3'-monophosphate (dG3'P-N2-N-dMeTAM), and alpha-(N2-deoxyguanosinyl)tamoxifen N-oxide 3'-monophosphate', and is capable of determining TAM adducts quantitatively. The detection limit of this assay is 0.6 adducts/10(9) nucleotides. trans-dG3'P-N2-TAM (fr-2; one of the two trans-isomers) was detected in six of 47 breast cancer patients treated with TAM. Among them, trans-dG(3'P-N2-N-dMeTAM (fr-2) was also detected in two patients. The total amounts of TAM-DNA adducts in the positive patients were 2.6 +/- 3.0 adducts/10(9) nucleotides. No adducts were detected in the controls. The presence of TAM-DNA adducts in the leukocyte DNA samples was confirmed using several 32P-postlabeling/HPLC systems.
