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)

(S)-10-(2,6-Dimethyl-4-pyridinyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H - pyrido[1,2,3-de][1,4]benzothiazine-6-carboxylic acid (WIN 58161) is an enantiomerically pure quinolone with outstanding bacterial topoisomerase II (DNA gyrase, EC 5.99.1.3) inhibitory and antibacterial activity. Unlike most quinolones, WIN 58161 also exhibits significant inhibitory activity against mammalian topoisomerase II (EC 5.99.1.3). DNA gyrase and topoisomerase II inhibitory activities are enantioselective. Consequently, WIN 58161 and its enantiomer (WIN 58161-2) provide useful tools to probe the contribution of topoisomerase II inhibition to the mechanism of cytotoxicity of quinolones and the potential utility of quinolone-topoisomerase II inhibitors as antitumor agents. WIN 58161 inhibited both highly purified Escherichia coli DNA gyrase and HeLa cell topoisomerase II by the promotion of enzyme-DNA covalent complexes. WIN 58161 did not bind stably to DNA via intercalation and did not enhance the formation of topoisomerase I (EC 5.99.1.2)-DNA covalent complexes. At drug concentrations that are cytotoxic to P388 murine leukemia cells, WIN 58161 promoted intracellular DNA single-strand breaks (SSBs) that exhibited the hallmarks of being mediated by topoisomerase. DNA fragments were complexed with protein, and SSBs were readily resealed at 37 degrees following drug removal. WIN 58161-2 was neither cytotoxic nor did it promote intracellular SSBs in P388. These observations suggest that the mechanism of cytotoxicity of WIN 58161 is predominantly, if not exclusively, a result of topoisomerase II inhibition. When studied in tumor-bearing mice, WIN 58161 exhibited a significant antitumor effect against each of five tumors tested, whereas neither toxicity nor antitumor activity was observed with WIN 58161-2. We conclude from these studies that WIN 58161 represents the prototype of a novel chemical class of topoisomerase II inhibitor with potential clinical utility in treating cancer.
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PMID:Mechanism of action and antitumor activity of (S)-10-(2,6-dimethyl-4-pyridinyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7 H- pyridol[1,2,3-de]-[1,4]benzothiazine-6-carboxylic acid (WIN 58161). 760 36

Thioxanthones are aromatic hydrocarbons with cytotoxic activity against several tumor models. Potential mechanisms of action may include DNA intercalation, inhibition of nucleic acid biosynthesis, and topoisomerase inhibition, as well as formation of intracellular DNA single strand breaks. Such a broad spectrum of expected antitumor activity makes this class of compounds particularly interesting and worth pursuing in clinical studies. SW 33377 (Win 33377, SR 233377) was so promising in vitro that it was taken into Phase I clinical trials for further evaluation. The compound had undesirable cardiac effects, so new analogs were sought that would have similar antitumor effects without the undesirable side effects. In the present study, two new analogs SW 68210 (WIN 68210), and SW 71425 (WIN 71425) are compared to the antiproliferative action of SW 33377 against a variety of freshly explanted human tumor specimens using an in vitro soft agar cloning system. All compounds were more effective with continuous exposure than 1 hour exposure and a concentration-response effect was evident with all compounds. SW 68210 with continuous exposure showed similar activity to SW 33377 at all concentrations. SW 71425 with continuous exposure was less effective at the lower concentrations but was nearly as effective at 10 microg/ml as the other two compounds and was highly effective at 50 microg/ml. At the 10 microg/ml concentration all compounds were similarly effective against breast, colon, non-small cell lung, and ovarian tumors. The two new analogs, SW 68210 and SW 71425 have activity similar to SW 33377 and are both likely candidates for further development.
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PMID:Effects of SW 33377, SW 68210 and SW 71425 thioxanthones on in vitro colony formation of freshly explanted human tumor cells. 1036 Jun 1

Our aim was to evaluate the roles of the cannabinoid pathway in the induction and propagation of systemic sclerosis (SSc) in a mouse model of diffuse SSc induced by hypochlorite injections. BALB/c mice injected subcutaneously every day for 6 weeks with PBS or hypochlorite were treated intraperitoneally with either WIN-55,212, an agonist of the cannabinoid receptors 1 (CB1) and receptors 2 (CB2), with JWH-133, a selective agonist of CB2, or with PBS. Skin and lung fibrosis were then assessed by histological and biochemical methods, and the proliferation of fibroblasts purified from diseased skin was assessed by thymidine incorporation. Autoantibodies were detected by ELISA, and spleen cell populations were analyzed by flow cytometry. Experiments were also performed in mice deficient for CB2 receptors (Cnr2(-/-)). Injections of hypochlorite induced cutaneous and lung fibrosis as well as increased the proliferation rate of fibroblasts isolated from fibrotic skin, splenic B cell counts, and levels of anti-DNA topoisomerase-1 autoantibodies. Treatment with WIN-55,212 or with the selective CB2 agonist JWH-133 prevented the development of skin and lung fibrosis as well as reduced fibroblast proliferation and the development of autoantibodies. Experiments performed in CB2-deficient mice confirmed the influence of CB2 in the development of systemic fibrosis and autoimmunity. Therefore, we demonstrate that the CB2 receptor is a potential target for the treatment of SSc because it controls both skin fibroblast proliferation and the autoimmune reaction.
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PMID:Targeting the cannabinoid pathway limits the development of fibrosis and autoimmunity in a mouse model of systemic sclerosis. 2050 30