Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:5.99.1.3 (topoisomerase)
 9,911 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1,25-Dihydroxyvitamin D3 (1,25(OH)2D3), the hormonal form of vitamin D, has anticancer activity in vivo and in vitro. Doxorubicin exerts its cytotoxic effect on tumor cells mainly by two mechanisms: (a) generation of reactive oxygen species (ROS); and (b) inhibition of topoisomerase II. We studied the combined cytotoxic action of 1,25(OH)2D3 and doxorubicin on MCF-7 breast cancer cells. Pretreatement with 1,25(OH)2D3 resulted in enhanced cytotoxicity of doxorubicin. The average enhancing effect after a 72-h pretreatment with 1,25(OH)2D3 (10 nM) followed by a 24-h treatment with 1 microg/ml doxorubicin was 74+/-9% (mean +/- SE). Under these experimental conditions, 1,25(OH)2D3 on its own did not affect cell number or viability. 1,25(OH)2D3 also enhanced the cytotoxic activity of another ROS generating quinone, menadione, but did not affect cytotoxicity induced by the topoisomerase inhibitor etoposide. The antioxidant N-acetylcysteine slightly reduced the cytotoxic activity of doxorubicin but had a marked protective effect against the combined action of 1,25(OH)2D3 and doxorubicin. These results indicate that ROS are involved in the interaction between 1,25(OH)2D3 and doxorubicin. 1,25(OH)2D3 also increased doxorubicin cytotoxicity in primary cultures of rat cardiomyocytes. Treatment of MCF-7 cells with 1,25(OH)2D3 alone markedly reduced the activity, protein, and mRNA levels of the cytoplasmic antioxidant enzyme Cu/Zn superoxide dismutase, which indicated that the hormone inhibits its biosynthesis. This reduction in the antioxidant capacity of the cells could account for the synergistic interaction between 1,25(OH)2D3 and doxorubicin and may also suggest increased efficacy of 1,25(OH)2D3 or its analogues in combination with other ROS-generating anticancer therapeutic modalities.
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PMID:1,25-Dihydroxyvitamin D3 enhances the susceptibility of breast cancer cells to doxorubicin-induced oxidative damage. 1002 76

Previous studies from this laboratory as well as others have demonstrated that breast tumor cells fail to undergo primary apoptosis in response to agents which induce DNA damage such as ionizing radiation and the topoisomerase II inhibitor adriamycin. Similarly, the primary response of breast tumor cells to vitamin D(3) [1,25-(OH)(2)-D(3)] and its analogs such as EB 1089 is growth inhibition, with apoptosis occurring in only a small fraction of the cell population. The possibility that the combination of vitamin D(3) compounds with radiation might promote cell death (i.e. through a differentiation stimulus plus DNA damage) was investigated by exposing both TP53 (formerly known as p53) wild-type and TP53 mutated breast tumor cells to 1,25-(OH)(2)-D(3) or EB 1089 for 48 h prior to irradiation. This combination resulted in enhanced antiproliferative effects in the TP53 wild-type MCF-7 cells based on both a clonogenic assay and the determination of numbers of viable cells. The combination of EB 1089 with radiation increased DNA fragmentation based on both the terminal transferase end-labeling (TUNEL) and bisbenzamide spectrofluorometric assays, suggesting the promotion of apoptosis. The observed increase in DNA fragmentation was not due to an enhancement of the extent of initial DNA damage induced by radiation. These findings suggest that vitamin D compounds may be useful in combination with radiation in the treatment of breast cancer.
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PMID:The vitamin D3 analog EB 1089 enhances the response of human breast tumor cells to radiation. 1052 24

Human topoisomerase IIIalpha (huTop IIIalpha) has been demonstrated to belong to type IA subfamily. In this study, we found that huTop IIIalpha expressed constitutively and remained at high levels throughout the cell cycle in HL-60 cells when compared to the cell-cycle-dependent expression of huTop IIIalpha in phytohemagglutinin-activated peripheral blood lymphocytes. During the cell cycle progression, this protein remained accentuated in the nucleolus without significant translocation from the nucleolus to the nucleoplasm. In addition, during the course of granulocytic maturation in DMSO-treated HL-60 cells, huTop IIIalpha levels decreased when cells stopped proliferation and nucleoli diminished in size. However, its level remained unchanged during the course of monocytic maturation of vitamin D(3)-treated HL-60 cells which still retained its proliferative capacity and did not change the size of the nucleolus. The data suggested that huTop IIIalpha is involved in rDNA metabolism, such as rDNA transcription. Its cellular level appeared to be under control during the cell cycle progression of normal lymphocytes, but was found to be deregulated in HL-60 cells which may be associated with the tumor transformed cell phenotypes.
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PMID:Differential expression of human topoisomerase IIIalpha during the cell cycle progression in HL-60 leukemia cells and human peripheral blood lymphocytes. 1073 69

Chemoprevention of prostate cancer is the administration of agents to prevent, inhibit, or delay progression of prostate cancer. Asian men have a much lower incidence of prostate cancer than men in Europe or the USA. Asian food includes low-fat, high-fiber diets, which provide a rich supply of weak dietary estrogens. These estrogens have been proposed as chemopreventive agents. In addition to their estrogenic activity, many of these plant compounds can interfere with steroid metabolism and bioavailability and can also inhibit enzymes, such as tyrosine kinase or topoisomerase, which are important for cellular proliferation. In addition, nutritional factors such as reduced fat intake, vitamin E, vitamin D, and selenium may have a protective effect against prostate cancer. The fact was proven in large epidemiological studies as well as experimental observations. In the animal model, the progression of established tumors can be inhibited by these agents. A number of studies to investigate the effect of possible chemopreventive agents for men at high risk of prostate cancer are established. End points for evaluation are mainly based on changes in PSA, changes of histological precursors, or time of onset of clinical disease. The concept of chemoprevention in prostate cancer might have a significant impact on the incidence and mortality of this disease.
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PMID:[Chemoprevention of prostatic carcinoma]. 1095 70

Pancreatic cancer is a common, highly lethal disease that is rising in incidence. Chemotherapy based on 5-fluorouracil (5-FU) has been shown to prolong survival in advanced pancreatic cancer. Gemcitabine improves major symptoms and survival outcomes compared with bolus 5-FU. Many novel small molecules are being widely and actively researched. These compounds are based on classical mechanisms of action as well as biological therapies targeting novel cellular survival pathways, and include fluoropyrimidines, nucleoside cytidine analogues, platinum analogues, topoisomerase-inhibitors, antimicrotubule agents, proteasome inhibitors, vitamin D analogues, arachidonic acid pathway inhibitors, histone deacytylator inhibitors, farnesyltransferase inhibitors and epidermal growth factor receptor therapies. Adjuvant chemotherapy has also demonstrated the best survival outcomes following resection compared to other adjuvant or neo-adjuvant strategies such as radiation-based treatments. These benefits are superimposed on the dramatic increase in resectability rates and reduction in post-operative mortality achieved by centralisation of treatment in high-volume speciality centres. Newer 'small-molecule' drugs as well as the latest 'large-molecule' biological agents hold considerable promise for the future. Real advances are anticipated over the next five years but are dependent on large randomised controlled trials for success.
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PMID:Review article: chemotherapy for pancreatic cancer. 1465 25

Hypoparathyroidism in systemic sclerosis is extremely rare with only a single case reported till date. Idiopathic hypoparathyroidism with systemic sclerosis was diagnosed in a 59-year-old gentleman who had presented with recurrent seizures, instability of gait, skin thickening and tightening over both legs and forearms, and arthritis. Examination was significant for positive Trousseau sign and cerebellar ataxia. Evaluation revealed bilateral symmetrical cerebellar and basal ganglia calcification, sensorineural deafness, low serum calcium, elevated serum phosphorus, normal magnesium, normal vitamin D, low plasma parathyroid hormone, high titer of thyroid peroxidase antibody, positive centromere pattern antinuclear antibody, strongly positive anti-topoisomerase-1 (Scl-70) antibody, nonvisualization of parathyroids on neck ultrasonography and skin biopsy suggestive of hyperkeratosis, increased collagen in dermis, and perivascular lymphomononuclear cell infiltration compatible with scleroderma. Last evaluated 10 months after the diagnosis, his ataxia had improved, he remained seizure-free, Trousseau sign was negative, and he had low-normal calcium calcium with calcium carbonate and calcitriol supplementation and switch from phenytoin to valproate. Further studies are warranted to study the use of serum calcium as a screening test for hypoparathyroidism in patients with systemic sclerosis.
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PMID:Idiopathic hypoparathyroidism and systemic sclerosis: An association likely missed. 2356 41