Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:5.99.1.2 (topoisomerase)
 9,166 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Breast irradiation, adjuvant chemotherapy, and tamoxifen are associated with an increased risk of second cancers that may manifest decades after treatment. Although very small, it is nonetheless important for clinicians and women to be aware of and to recognize the risk. Postmastectomy irradiation is associated with a slight increase in the risk of developing a sarcoma or lung cancer after a latency period of more than 10 years. However, the majority of information on radiation-associated cancers is derived from large tumor registries, which reflect outdated radiation treatment practices. Modern treatment approaches, which use lower fraction size (or dose) and limit the exposure of surrounding normal tissue to radiation, are less likely to cause radiation-associated cancers. Adjuvant chemotherapy is not associated with any detectable increased risk of solid tumors beyond that which occurs as the population ages. However, alkylating agents, such as cyclophosphamide, and the topoisomerase II inhibitors, doxorubicin and epirubicin, are associated with two types of cytogenetically distinct leukemias after adjuvant chemotherapy. The absolute risk of developing leukemia is lower by orders of magnitude than the improvement in breast cancer mortality that results from adjuvant chemotherapy. Tamoxifen is associated with a two- to threefold increase in the risk of developing endometrial cancer, or about 80 excess cases per 10,000 treated women at 10 years. The benefits of adjuvant therapy outweigh the risks of developing second cancers. Additional studies are needed to more precisely identify patients who are or are not likely to benefit from adjuvant therapy, and individual host and treatment factors that influence the development of second cancer.
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PMID:Second cancers after breast cancer treatment. 1466 75

Although tamoxifen can trigger steatohepatitis, the mechanism of steatosis is unclear. We hypothesized that this DNA-intercalating, cationic amphiphilic drug could accumulate within mitochondria to impair fatty acid oxidation, respiration, and mitochondrial DNA relaxation and synthesis. We studied the in vitro effects of tamoxifen on topoisomerases and mouse liver mitochondria and its in vivo hepatic effects in mice treated for 1 to 28 days with a daily dose of tamoxifen reproducing the plasma concentrations observed in humans. In vitro, tamoxifen inhibited topoisomerase-mediated plasmid DNA relaxation. It accumulated 40-fold inside mitochondria and inhibited both respiration and fatty acid oxidation. In vivo, a single dose of tamoxifen inhibited palmitic acid oxidation and hepatic lipoprotein secretion. Tamoxifen administration also decreased mitochondrial DNA synthesis and progressively depleted hepatic mitochondrial DNA, down to 40% of control values at 28 days. The decrease in mitochondrial DNA-encoded respiratory complexes sensitized mitochondria to the inhibitory effects of tamoxifen on mitochondrial respiration. Hepatic steatosis was absent at 5 days, mild at 12 days, and moderate at 28 days. The fatty acid synthase protein was normally expressed at 12 days but was decreased by 52% at 28 days. In conclusion, tamoxifen decreases hepatic triglyceride secretion, and it accumulates electrophoretically in mitochondria, where it impairs beta-oxidation and respiration. Tamoxifen also inhibits topoisomerases and mitochondrial DNA synthesis and progressively depletes hepatic mitochondrial DNA in vivo. These combined effects could decrease fat removal from the liver, thus causing hepatic steatosis despite a secondary down-regulation of hepatic fatty acid synthase expression.
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PMID:Tamoxifen inhibits topoisomerases, depletes mitochondrial DNA, and triggers steatosis in mouse liver. 1727 97