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)

An actinomycin D selected, multidrug-resistant (MDR) hamster CHO subline showed strong expression of the P-glycoprotein and sorcin genes together with several other alterations such as a: (i) reduced growth rate, (ii) lowered topoisomerase II, (iii) lowered glutathione-S-transferase-P gene expression, and (iv) the emergence of a 15.5 kDa protein. Besides high resistances to adriamycin, actinomycin D, and vincristine, we observed a lowered sensitivity towards bleomycin, a rather hydrophilic drug usually not involved in P-glycoprotein associated MDR. Moreover, the MDR subline showed a pronounced collateral (enhanced) sensitivity towards the sterically pure dihydropyridine anticancer drug dexniguldipine-HCl (B859-35) preventing its characterization for MDR modulation here. At a non-cytotoxic dose (10 microM) the immunosuppressive cyclic peptide cyclosporin A completely abolished the resistance to vincristine, partially reversed the resistance to teniposide and strongly enhanced the sensitivity towards bleomycin, while not influencing the drug sensitivities of the parental cell line. Buthionine sulfoximine (BSO), an agent depleting cellular glutathione levels, distinctly increased the sensitivity towards teniposide at nontoxic doses (50 microM) exclusively in the MDR subline, while it did not alter vincristine or bleomycin cytotoxicity.
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PMID:MDR hamster cells exhibiting multiple altered gene expression: effects of dexniguldipine-HCl (B859-35), cyclosporin A and buthionine sulfoximine. 128 2

Chemotherapy failure remains a significant medical problem in the treatment of neoplastic disease and is thought to be due to many different factors including membrane transport, p-glycoprotein in multidrug resistance, glutathione and its related enzymes, topoisomerase II and DNA repair. Glutathione is a major constituent of non-protein thiol and participates in detoxification of chemotherapy and radiation. Thus, glutathione concentration is correlated with sensitivity to alkylating agents and radiation, and increased in resistant cell lines. Buthionine sulfoximine (BSO) is an inhibitor of glutathione biosynthesis and may increase cytotoxicities of alkylating agents, including melphalan and cisplatin, and radiation in sensitive and resistant cell lines. We studied effects on cellular glutathione levels and cytotoxicities of cisplatin, carboplatin and radiation by BSO treatment in human stomach cancer cell line (SNU-1) and ovarian cancer cell line (OVCAR-3). The results were as follow: 1) After BSO treatment of 1 mM and 2 mM for 2 days, the intracellular thiol concentration was depleted to 75.7% and 76.2% in SNU-1, and 74.1% and 63.0% in OVCAR-3, respectively. 2) The intracellular thiol concentration in SNU-1 was depleted to 33.4% after BSO 2 mM for only 2 hours incubation and 71.5% after small amount of BSO (0.02 mM) for 2 days. 3) The recovery of intracellular thiol concentration required more than 3 days after BSO removal. 4) BSO inhibited partially the growth of SNU-1 and OVCAR-3. 5) The cytotoxicities of cisplatin and carboplatin were markedly enhanced both in SNU-1 and OVCAR-3 by BSO treatment. 6) The cytotoxicities of radiation was increased in OVCAR-3 and SNU-1 by BSO treatment. Therefore, it is concluded that BSO can deplete effectively the intracellular thiol concentration and enhance the cytotoxicities of cisplatin, carboplatin and radiation.
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PMID:Effects of buthionine sulfoximine treatment on cellular glutathione levels and cytotoxicities of cisplatin, carboplatin and radiation in human stomach and ovarian cancer cell lines. 130 72

Depletion of glutathione (GSH) in MCF-7 and MDA-MB-231 cell lines by pretreatment with the GSH synthesis inhibitor buthionine sulfoximine potentiated the activity of 10,11-methylenedioxy-20(S)-camptothecin, SN-38 [7-ethyl-10-hydroxy-20(S)-camptothecin], topotecan, and 7-chloromethyl-10,11-methylenedioxy-20(S)-camptothecin (CMMDC). The greatest potentiation was observed with the alkylating camptothecin CMMDC. Buthionine sulfoximine pretreatment also increased the number of camptothecin-induced DNA-protein crosslinks, indicating that GSH affects the mechanism of action of camptothecin. We also report that GSH interacts with CMMDC to form a stable conjugate, 7-(glutathionylmethyl)-10,11-methylenedioxy-20(S)-camptothecin (GSMMDC), which is formed spontaneously in buffered solutions and in MCF-7 cells treated with CMMDC. GSMMDC was synthesized and found to be nearly as active as 10,11-methylenedioxy-20(S)-camptothecin in a topoisomerase (topo) I-mediated DNA nicking assay. The resulting topo I cleavage complexes were remarkably stable. In cell culture, GSMMDC displayed potent growth-inhibitory activity against U937 and P388 leukemia cell lines. GSMMDC was not active against a topo I-deficient P388 cell line, indicating that topo I is its cellular target. Peptide-truncated analogues of GSMMDC were prepared and evaluated. All three derivatives [7-(gamma-glutamylcysteinylmethyl)-10,11-methylenedioxy-20(S)-camptothecin, 7-(cysteinylglycylmethyl)-10,11-methylenedioxy-20(S)-camptothecin, and 7-(cysteinylmethyl)-10,11-methylenedioxy-20(S)-camptothecin] displayed topo I and cell growth-inhibitory activity. These results suggest that 7-peptidyl derivatives represent a new class of camptothecin analogues.
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PMID:Dual role of glutathione in modulating camptothecin activity: depletion potentiates activity, but conjugation enhances the stability of the topoisomerase I-DNA cleavage complex. 1246 34