Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

4'-(9-Acridinylamino)methanesulfon-m-anisidide (m-AMSA) is a DNA intercalating 9-aminoacridine with clinical activity in adult acute leukemia. m-AMSA has been shown to produce protein-linked DNA strand breaks in mammalian cells through an interaction with the nuclear enzyme DNA topoisomerase II. We have compared the effects of m-AMSA and several acridine analogues (9-aminoacridine; A, NSC 343499; B, SN 16507; C, NSC 140701; D, SN 13553) on DNA integrity and cell survival in L1210 leukemia in vitro. Cells (or isolated nuclei) were treated with drugs (0.1-50 microM) for 0.5-1.0 h and subsequently analyzed using the alkaline elution technique. All drugs, except Compound D, produced DNA-protein cross-links (DPC) in L1210 cells. At 1 microM, potency was in the order, C greater than m-AMSA greater than B greater than A much greater than 9-aminoacridine. In isolated nuclei, DPC and single-strand breaks were produced in essentially a 1:1 ratio, which is consistent with topoisomerase II-mediated protein-linked DNA breaks. Potency differences were less pronounced in nuclei than in cells. In isolated nuclei, Compound D produced extensive DPC not associated with single-strand breaks, which suggests a more complex activity for this compound. Colony formation assays demonstrated the cytotoxicity of most of these acridine analogues (C greater than B greater than A approximately equal to m-AMSA much greater than D = 9-aminoacridine). Correlation of DPC with cell kill gave similar curves for each compound. These results are evidence for a causal relationship between drug-induced topoisomerase II-mediated DNA breaks and cytotoxicity.
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PMID:Topoisomerase II-mediated DNA damage produced by 4'-(9-acridinylamino)methanesulfon-m-anisidide and related acridines in L1210 cells and isolated nuclei: relation to cytotoxicity. 282 87

The N-acylanthracyclines AD32 (N-trifluoroacetyladriamycin-14-valerate) and AD143 (N-trifluoroacetyladriamycin-14-O-hemiadipate) are analogs of Adriamycin (ADR) undergoing clinical or advanced pre-clinical screening. Their principal metabolites, following the cleavage of the 14-acyl side-chain, are N-trifluoroacetyladriamycin (AD41) and its reduced form N-trifluoroacetyladriamycinol (AD92). Both these compounds are biologically active and detectable in treated patients, laboratory animals, and in tissue culture cells. Unlike ADR, AD32, as well as AD143 and metabolites, show no detectable binding to double-strand DNA. Their effects on DNA have been previously investigated in vivo and in vitro using the alkaline filter-elution assay. It has been shown that all of the compounds cause approximately equivalent amounts of protein-associated DNA breaks (PAB) and DNA-protein crosslinks in a mouse lymphoma and in tissue-culture leukemia cells. In order to establish whether the induction of PAB by the drugs requires DNA topoisomerase II mediation, cleavage mapping analysis was done with tested compounds using purified human topoisomerase II. DNA fragmentation was significantly enhanced in the presence of the enzyme and either AD41 or AD92. In contrast, no fragmentation enhancement was observed in the presence of the parental drugs AD32 or AD143. The results strongly suggest that metabolic activation of N-acylanthracyclines by nonspecific esterases is a prerequisite for their interaction with DNA topoisomerase II and for stabilization of the cleavable complex.
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PMID:Metabolic activation of N-acylanthracyclines precedes their interaction with DNA topoisomerase II. 304 Dec 37

The chemistry, pharmacology, pharmacokinetics, clinical efficacy, dosage and administration, and adverse effects of mitoxantrone are reviewed. Mitoxantrone, an aminoanthraquinone that was synthesized in 1979, belongs to a new chemical class of agents known as the anthracenediones. It possesses antiviral, antibacterial, immunomodulatory, and antitumor activity. The drug's antitumor activity is attributed to its interaction with DNA topoisomerase II, and its interaction with human cells may also involve nonintercalary, electrostatic interactions. Mitoxantrone is poorly absorbed orally and is most commonly administered intravenously. The drug is rapidly distributed into the red blood cells, white blood cells, and platelets, followed by deep-tissue sequestration. Mitoxantrone has demonstrated clinical efficacy in the treatment of leukemia, lymphoma, and breast cancer. As a single agent, mitoxantrone has a response rate of roughly 30% in acute nonlymphocytic leukemia or acute myeloid leukemia. In combination with other standard agents (cytarabine, vincristine, and prednisone), the response rate may reach 60%. In breast cancer, mitoxantrone's response rate as a single agent is 25-30%, while combination regimens produce response rates of 60% or more. The drug can cause cardiotoxicity with cumulative doses. Other adverse effects include myelosuppression, nausea and vomiting, stomatitis, mucositis, and alopecia. The cost of mitoxantrone is comparable to that of doxorubicin, but it is substantially more expensive than daunorubicin. Mitoxantrone is an important new agent with antitumor activity in leukemia, lymphoma, and breast cancer. In most situations, mitoxantrone will be considered second-line treatment or a restricted-use item because of its high cost and because of the lack of FDA approval for indications other than acute nonlymphocytic leukemia.
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PMID:Mitoxantrone: a novel anthracycline derivative. 304 48

The effects of various antileukemic agents on DNA replication associated with the nuclear matrix were investigated in CCRF-CEM leukemia cells. Residual nuclear matrices were prepared by sequential treatment of nuclei with 1.5 M NaCl, DNase I, and Triton X-100 and contained 1-5, 10, and 37% of the total nuclear DNA, protein, and phospholipid, respectively. In control cells pulse-labeled for 45 s with [3H]thymidine, the specific activity of nascent DNA was four-fold greater in the nuclear matrix fraction relative to the specific activity of the high salt-soluble (nonmatrix) DNA fraction. Pulse-labeling and reconstitution experiments indicated that this enrichment of newly replicated DNA on the nuclear matrix did not result from aggregation of nascent DNA with the matrix. A 2-h incubation of tumor cells with either 0.1 microM teniposide (VM-26), 0.2 microM VM-26, or 0.5 microM amsacrine (m-AMSA) reduced the relative specific activity of nascent DNA on the nuclear matrix by 59, 61, and 54%, respectively, compared to control cells. In contrast hydroxyurea and cytosine arabinoside, at concentrations that markedly inhibited total nuclear DNA synthesis, did not decrease the relative specific activity of newly replicated DNA on the matrix. The results provide evidence that the antiproliferative effects of the DNA topoisomerase II inhibitors, VM-26 and m-AMSA, are localized on the nuclear matrix of CCRF-CEM leukemia cells.
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PMID:Effects of antileukemia agents on nuclear matrix-bound DNA replication in CCRF-CEM leukemia cells. 334 63

The antitumor agent etoposide interacts with DNA topoisomerase II to produce a unique form of DNA-enzyme intermediate referred to as a "cleavable complex". These drug-induced DNA strand breaks initiate poorly defined cell processes which result in lethality. To explore the mechanism of etoposide cytotoxicity, we studied the effect of protein synthesis inhibitor on Balb/C 3T3 fibroblasts and CCRF-CEM and L1210 leukemia cells by exposing these cell lines to cycloheximide for various periods of time prior to etoposide challenge. Cycloheximide alone during these periods of exposure was not cytotoxic; however, it conferred increasing cytoprotection from etoposide in a time-dependent fashion when it preceded etoposide. Although cycloheximide did cause a decrease in enzyme content and in etoposide-induced DNA cleavage of Balb/C 3T3 and the CCRF-CEM cell lines, cytoprotection by cycloheximide could not be accounted for completely by these phenomena since, in L1210 cells, cytoprotection was observed without significant change in DNA cleavage or enzyme content. Cycloheximide diminished DNA synthesis as well as protein synthesis. However, DNA synthesis resumed within 6 hr after removal of cycloheximide, in spite of the fact that cytoprotection persisted. Cycloheximide did not alter cell cycle distribution as measured by flow cytometry. Our data, therefore, clearly demonstrate that cycloheximide can diminish the cytotoxic potential of etoposide-mediated topoisomerase-DNA complexes. Elucidation of the mechanism by which cytoprotection occurs should shed light on the basis for the cytotoxic effect of topoisomerase II-active drugs.
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PMID:Abrogation of etoposide-mediated cytotoxicity by cycloheximide. 335 86

Continuous cell lines are frequently contaminated with microorganisms, mycoplasmas being the most prominent and cumbersome. In our experience, of the 300 cell lines examined more than one third was infected with mycoplasmas. Mycoplasma contamination can affect virtually every parameter and functional activity of a cultured cell. An alternative to the recommended disposal of infected cultures is an attempt to eliminate the contaminants. Adding antibiotics with strong activity against mycoplasmas to the culture medium is a simple, inexpensive and efficient decontamination method. Here, we studied the effectiveness of the new antibiotic enrofloxacin (Baytril) developed specifically for use against mycoplasmas. Baytril is a new synthetic agent from the group of quinolone derivatives that are DNA gyrase inhibitors. Thirty-two chronically infected cell lines (27 human leukemia-lymphoma cell lines) were treated with Baytril in a prospective study in direct comparison with three other well-established anti-mycoplasma regimens, the antibiotics BM-Cyclin, Ciprobay and MRA (Mycoplasma Removal Agent). Mycoplasmas were detected by DNA staining, agar colony growth, DNA-RNA hybridization, polymerase chain reaction, and monoclonal antibody staining. Treatment with Baytril eliminated the contaminants in 30/32 cultures (94%). The cure rates for Ciprobay, BM-Cyclin and MRA were 91%, 81%, and 75%, respectively. The IC50 values of Baytril for cell lines varied over a wide range depending on the type of hematopoietic cell lineage with T- and B-cell lines being more sensitive targets. Baytril-treated cell lines remained mycoplasma-negative over a 12-week antibiotic-free culture period. Low levels of mycoplasma infection were shown not to persist by repeat testing after growth without antibiotics. A retrospective analysis of anti-mycoplasma treatments with BM-Cyclin, Ciprobay, MRA or Baytril showed that 265/351 cultures (75%) were immediately cured of mycoplasma; however, all of the remaining, mycoplasma-positive cultures harboring mycoplasms resistant to the first antibiotic could be cleaned up by a second round with a different antibiotic. Baytril is an efficient anti-mycoplasma antibiotic and based on its high cure rate might be the treatment of first choice.
Leukemia 1994 Aug
PMID:Effective treatment of mycoplasma contamination in cell lines with enrofloxacin (Baytril). 752 Jan 3

DNA topoisomerase II is a major protein of the nuclear matrix. The enzyme appears to have a central role in both DNA organization and replication. The importance of nuclear matrix topoisomerase II alpha as a target for certain anticancer agents was evaluated in CEM human leukemia cells. Studies were done to determine the extent to which the alpha (170 kDa) and beta (180 kDa) isozymes of topoisomerase II form covalent enzyme-DNA complexes in whole cells and in the nuclear matrix and nonmatrix fractions of CEM cells that are either sensitive or resistant to topoisomerase II-active anticancer agents. Topoisomerase II alpha was detected in both the high salt-soluble (nonmatrix) and matrix fractions of nuclei from parental CEM cells. Most of the matrix topoisomerase II alpha was tightly bound to DNA in cells incubated with VM-26. In contrast, topoisomerase II beta was detected only in the high salt-soluble (nonmatrix) fraction of the nucleus. The subnuclear distribution of the alpha and beta topoisomerase II isozymes in CEM/VM-1 cells resistant to topoisomerase-active drugs was similar to that in drug-sensitive CEM cells. However, the amount and activity of topoisomerase II alpha in nuclear matrices of CEM/VM-1 cells were decreased 3- to 6-fold relative to that of CEM cells. The differences observed in the subnuclear distribution and DNA binding pattern of the topoisomerase II isozymes support the hypotheses that each isozyme has a distinct cellular function. Furthermore, these results provide evidence that topoisomerase II alpha is the nuclear matrix target for VM-26, and that depletion of the nuclear matrix isozyme contributes to cellular resistance to this anticancer agent.
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PMID:DNA topoisomerase II isozymes involved in anticancer drug action and resistance. 757 48

(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

The possible intervention of nuclear proteins as cofactors of integrase-catalyzed integration of retroviral DNA into the host cell genome is not fully understood. Among various nuclear proteins, DNA topoisomerase II appears to be a plausible candidate. This hypothesis is supported by a series of evidence, including the fact that integration is markedly affected by the topology of the target DNA and mainly occurs in transcribed regions in which topoisomerase II is preferentially located. In an attempt to confirm the validity of this hypothesis, we have comparatively investigated the early stages of a recombinant Moloney murine leukemia virus (psi neo) in two related Chinese hamster cell lines (DC3F and R/DC3F) expressing different levels of both isoforms of topoisomerase II. R/DC3F is derived from the parental cell line DC3F and displays a resistant phenotype towards the usual anticancer topoisomerase II inhibitors (actinomycin D, doxorubicin, and taxol). Results show that the early stages of the retroviral cycle are markedly impaired in cells underexpressing topoisomerase II (R/DC3F). This alteration mimics Fv-1 restriction and is characterized by about a 6-fold decrease in viral DNA synthesis and total inhibition of viral genome integration. The specific impairment of integration in R/DC3F cells compared to DC3F cells is assessed by the absence of G418-resistant colonies upon viral infection and a lack of the viral genome in cellular nuclear DNA as detected by the PCR procedure. These features are observed in relevant infecting conditions leading, in both cell lines, to the same amount of linear viral DNA and to the occurrence of two long terminal repeats containing circular DNA in the nuclear fractions.
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PMID:Impairment of Moloney murine leukemia virus integration in a cell line underexpressing DNA topoisomerase II. 760 43

3'-Aminocyanoborane-2', 3'-dideoxythymidine (VIIa) and 3'-aminocyanoborane-2', 3'-dideoxyuridine (VIIIb) were successfully synthesized. The thymidine derivative (VIIIa) was shown to be a potent cytotoxic agent in murine and selected human suspended and solid tumor cell lines. Compound VIIIa inhibited L-1210 leukemia DNA and RNA synthesis with the protein synthesis requiring a higher concentration of drug for inhibition within 60 min. The purine pathway appeared to be the major target of Compound VIIIa with inhibition of IMP dehydrogenase and dihydrofolate reductase activities. The compound affected metabolic enzyme activities in the pyrimidine pathway as well as the nucleoside kinase activities. The DNA molecule did not appear to be target of the 3'-aminocyanoborane-2', 3'-dideoxythymidine (VIIIa), in that there was no change in ct-DNA viscosity, thermal denaturation or absorption of nucleosides of DNA nor was there any L-1210 DNA strand scission or inhibition of L-1210 DNA topoisomerase II activity when compound VIIIa was incubated at 100 microM.
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PMID:The cytotoxicity of 3'-aminocyanoborane-2', 3'-dideoxypyrimidines in murine and human tissue cultured cell lines. 764 85


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