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)

Sensitive (P388/S) and amsacrine-resistant (P388/amsacrine) sublines of P388 leukemia were cloned in vitro and tested for differential chemosensitivity against a panel of drugs. P388/amsacrine, resistant both in vivo and in vitro to amsacrine, was cross-resistant to other putative topoisomerase II inhibitors including teniposide, etoposide, bisantrene, and doxorubicin. P388/amsacrine, was however, as sensitive as cloned P388/S to camptothecin, an inhibitor of topoisomerase I. The pattern of cross-resistance suggested that an alteration in topoisomerase II may be involved in the resistance of P388/amsacrine to these drugs. No differences in the uptake of amsacrine were detected between the two sublines. Cross-resistance to vinblastine was evident in P388/amsacrine; however resistance to vinblastine was associated with alterations in uptake or efflux of the drug. The number of protein-concealed single-strand breaks induced in whole cells by amsacrine, teniposide, bisantrene, and camptothecin was measured. Diminished numbers of strand breaks in the resistant subline were consistent with decreases in DNA-protein crosslinks. In the absence of drug treatment, resistant cells sustained approximately one-half as many single-strand breaks and DNA-protein crosslinks as the sensitive cells during preparation of nuclei. As measured by the P4 phage DNA unknotting assay, 0.35 M NaCl nuclear extracts from P388/S contained approximately 2.3-fold more topoisomerase II catalytic activity than did extracts from P388/amsacrine. The amount of protein that immunoreacted with a specific antibody to calf thymus topoisomerase II was also decreased in the resistant cells. These data suggest that alterations in topoisomerase II which lead to differential drug sensitivities are partially responsible for the resistance of P388/amsacrine to a specific group of drugs.
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PMID:Characterization of a subline of P388 leukemia resistant to amsacrine: evidence of altered topoisomerase II function. 303 2

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

A number of new anilino ring variants of the anti-tumour drug amsacrine have been synthesised and their anti-tumour activity evaluated. In vitro selectivity, as measured by the logarithmic ratio of IC50 growth inhibition assays against P388 leukaemia and Lewis lung carcinoma cells, was significantly correlated with the increase in life span in vivo with the P388 leukaemia and Lewis lung lines, whereas the growth inhibition IC50 values alone correlated with the dose potency in mice. It was thus possible to predict both in vivo anti-tumour activity and dose potency, identifying compounds with high therapeutic activity, using a combination of two in vitro assays. Two new compounds have been identified which provide, along with an acridine-substituted analogue of amsacrine which is at present in clinical trial (CI-921), a high proportion of cures against the Lewis lung tumour in vivo. Since amsacrine is thought to interact with the enzyme topoisomerase II, and because the anilino group of 9-anilinoacridine derivatives is thought to project from the DNA intercalation site of the drug-DNA complex, these compounds may be of particular interest in mode of action studies.
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PMID:In vitro and in vivo assessment of activity of new anilino-substituted analogues of amsacrine against Lewis lung carcinoma. 345 Feb 94

2-(Diethylamino-2-ethyl)9-hydroxyellipticinium-chloride, HCl (DHE), a new congener of the antitumor agent elliptinium acetate (Celiptium) (NMHE), has recently been selected for phase I clinical trials. NMHE has a methyl group at nitrogen 2 on the ellipticine ring while DHE possesses a basic diethylaminoethyl chain at this position. Compared to NMHE, the presence of the diethylaminoethyl side chain results in the following: a significant increase in the lipophilicity of the drug; no significant modification in either the binding constant values to DNA or the ability to intercalate between DNA base pairs; a marked decrease in the unwinding angle value of supercoiled DNA; and no significant change in the alteration of the catalytic activity of topoisomerase II in vitro. DHE appears to act as a simple reversible intercalating agent as shown by the selective mutagenic effect on Salmonella TA 1977 tester strain and by its inability to induce the SOS functions in a sfiA lac fusion containing Escherichia coli strain. From a pharmacological point of view, the presence of the diethylaminoethyl chain results in a 2-fold increase in the cytotoxicity to L1210 cultured cells, a strong increase in the antitumor efficiency on experimental murine tumors such as L1210 and P388 leukemia, B16 melanoma, M 5076 reticulosarcoma, and colon 38 adenocarcinoma, and finally an objective decrease in the acute and subacute toxicity in mice, rat, and macaque. The absence of significant differences in the interaction of NMHE and DHE with their potential targets in vitro leads to the hypothesis that the superiority of DHE in terms of cytotoxicity and antitumor efficiency may be due to an increase in the diffusion across cellular membrane and a more favorable biodistribution in vivo.
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PMID:Physicochemical and pharmacological properties of the antitumor ellipticine derivative 2-(diethylamino-2-ethyl)9-hydroxy ellipticinium-chloride, HCl. 367 74

Mitochondria from human acute lymphoblastic leukemia cells contain an ATP-independent DNA topoisomerase which can relax negative and positive supercoils. This enzyme has been purified 200-fold by carboxymethyl-cellulose or double stranded DNA-cellulose chromatography. In contrast to the molecular weights reported for mitochondrial topoisomerases in other systems, the native leukemia enzyme has a molecular weight of 132,000 daltons as determined by gel permeation chromatography in buffer containing 0.4 M KC1. It also exhibits a sedimentation coefficient of 7.1 S when centrifuged through a 10-30% glycerol gradient in this high salt buffer. The enzyme is presumably a type I topoisomerase analogous to those found in rat liver and Xenopus laevis mitochondria.
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PMID:Isolation of a mitochondrial DNA topoisomerase from human leukemia cells. 632 1

We selected and characterized a 30-fold etoposide (VP-16)-resistant subline of K562 human leukemia cells (K/VP.5) that exhibits quantitative and qualitative changes in topoisomerase II, including hypophosphorylation of this drug target. The initial rate of topoisomerase II phosphorylation was reduced 3-fold in K/VP.5 compared with K562 cells, but the rate of dephosphorylation was similar. Analysis of potential topoisomerase II protein kinases revealed a 3-fold reduction in the level of the beta II protein kinase C (PKC) in K/VP.5 cells, whereas levels of alpha- and epsilon PKC, casein kinase II, p42map kinase, and p34cdc2 kinase were comparable for both cell lines. The PKC activator, bryostatin 1, together with K562 nuclear extracts potentiated VP-16-induced topoisomerase II/DNA covalent complex formation in nuclei isolated from K/VP.5 cells but not from K562 cells. Bryostatin 1 effects were blocked by the PKC inhibitor 7-O-methyl-hydroxy-staurosporine. Bryostatin 1 also up-regulated topoisomerase II phosphorylation and potentiated VP-16 activity in intact K/VP.5 cells but had no enhancing effect in K562 cells. 4 beta-Phorbol-12,13-dibutyrate and 12-O-tetradecanoylphorbol-13-acetate did not potentiate VP-16-induced topoisomerase II/DNA complex formation in intact cells or in isolated K/VP.5 nuclei. Together, our results indicate that beta II PKC plays a role in modulating the VP-16-induced DNA binding activity of topoisomerase II in resistant K/VP.5 cells through a mechanism linked to phosphorylation of topoisomerase II.
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PMID:Hypophosphorylation of topoisomerase II in etoposide (VP-16)-resistant human leukemia K562 cells associated with reduced levels of beta II protein kinase C. 747 9

It has been reported that human promyelocytic leukemic HL-60 cells which undergo differentiation fail to respond by apoptosis when treated with antitumor drugs, predominantly DNA topoisomerase inhibitors. Because S phase cells are selectively sensitive to these drugs, and during differentiation there is a reduction in the proportion of cells in S phase, the reported decrease in the number of apoptotic cells could simply be a reflection of the paucity of sensitive cells in these cultures. Using cytometric methods which allow apoptosis to be related to cell cycle position, we have compared the apoptotic response of HL-60 cells growing exponentially and induced to myeloid differentiation by dimethyl sulfoxide (DMSO). The cells were treated with: (i) the DNA topoisomerase I inhibitor camptothecin (CAM), which selectively triggers apoptosis or S phase cells; (ii) the nucleoside antimetabolite 5-azacytidine (AZC) and hyperthermia, both of which preferentially affects G1 cells; and (iii) gamma radiation, which causes apoptosis predominantly of G2 + M cells. The cells exposed to 1.4% DMSO for 24 or 48 h were significantly more resistant to response by apoptosis, regardless of the nature of the agent and regardless of their position in the cell cycle. Thus, induction of differentiation lowers the cell's ability to respond to a variety of damaging agents by apoptosis and this effect is not correlated with cell cycle position. In addition, the difference in response was unrelated to expression of the apoptosis-modulating protein bcl-2, which appeared unchanged following 48 h exposure to DMSO. On the other hand, when the cells were pretreated with low concentrations of CAM or AZC, washed free of drug, and then treated with DMSO, the proportion of cells undergoing apoptosis was markedly increased, relative to drug-treated cells returned to DMSO-free medium. The present data may indicate that while the drug-induced damage screening mechanisms, which are linked to triggering apoptosis, may be more proficient in proliferating cells, the effectors of apoptosis are more expressed in cells undergoing differentiation. The data also suggest that the efficiency of chemotherapeutic agents or radiation may be reduced if a differentiating agent is used in combination therapy and is administered first. An enhancement of apoptosis, however, may be expected if the differentiating drug is administered in the reverse sequence.
Leukemia 1994 Feb
PMID:Altered susceptibility of differentiating HL-60 cells to apoptosis induced by antitumor drugs. 750 35


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