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)

Exposure of human promyelocytic leukemic HL-60 cells to the topoisomerase I inhibitor camptothecin (CAM) triggers endonucleolytic activity and apoptotic death of these cells. The nucleolytic effect is seen 2-4 h after drug addition and is highly selective to cells progressing through S phase. Concomitant with degradation of DNA, which is preferential to the nucleosomal DNA linker sections, extensive proteolysis takes place in these cells. Cellular RNA, however, is initially degraded to a much lesser degree than DNA or protein. Both endonucleolysis and proteolysis triggered by CAM in S-phase HL-60 cells can be prevented by the protease inhibitors N-tosyl-L-phenylalanylchloromethyl ketone (TPCK), N-tosyl-L-lysylchloromethyl ketone (TLCK) or partly by N-tosyl-L-arginine methyl ester (TAME), added simultaneously with CAM, or up to 30 min after exposure to CAM, at their respective concentrations known to inhibit proteases. The protective effect of these protease inhibitors on DNA degradation cannot be due to the suppression of cell progression through S phase because cells still replicate DNA in their presence, albeit at a reduced rate. Furthermore, TPCK and TLCK protect rat thymocytes against endonucleolysis induced by prednisolone. In the latter cell system, (considered a classic model of apoptosis), endonucleolysis, which primarily affects G0/G1 cells, is unrelated to cell progression through S phase. The present data suggest that the endonucleolysis and proteolysis which accompany apoptotic cell death are coupled, and the proteolytic step is needed for DNA degradation to occur.
Leukemia 1992 Nov
PMID:Inhibitors of proteases prevent endonucleolysis accompanying apoptotic death of HL-60 leukemic cells and normal thymocytes. 127 23

A subline of P388 leukemia made 10-fold resistant to camptothecin (CPT) by serial passage in drug-treated mice was adapted to growth in tissue culture and made hyper-resistant to CPT by passage in the presence of increasing concentrations of the drug. Cells were obtained that were 1,000-fold resistant to CPT, compared to wild-type P388 cells. Neither topoisomerase I mRNA nor 100 kDa topoisomerase I enzyme was detectable in these cells, and topoisomerase I activity extracted from nuclei was less than 4% of that extracted from nuclei of wild-type cells. An immunoreactive 130 kDa protein that could be an altered, inactive form of topoisomerase I was evident in the hyper-resistant cells. In addition, the cells deficient in topoisomerase I contained enhanced topoisomerase II activity. Maintenance of the hyper-resistant phenotype required continued exposure to CPT; growth in its absence led to loss of hyper-resistance, increased topoisomerase I content and activity, and decreased topoisomerase II activity. The sensitivity of the cells to killing by a number of inhibitors of topoisomerases I and II was consistent with these observations. Thus, P388 cells have the potential to become highly resistant to CPT by severely curtailing topoisomerase I expression; in these circumstances, topoisomerase I and II activities are regulated coordinately.
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PMID:Camptothecin hyper-resistant P388 cells: drug-dependent reduction in topoisomerase I content. 133 78

Topotecan (TPT, 9-dimethylaminomethyl-10-hydroxycamptothecin) is the first topoisomerase I-directed cytotoxic agent to enter clinical trials in the United States in two decades. The effect of P-glycoprotein (Pgp) overexpression on TPT cytotoxicity was examined in CHRC5 (colchicine-resistant) and AuxB1 (parental) Chinese hamster ovary cells. Examination of the IC50 values observed in colony-forming assays revealed that the CHRC5 cells were 15-fold (SD, +/- 3; n = 3) resistant to TPT after a 1-h exposure and 3.2-fold (SD, +/- 1.4; n = 4) resistant in continuous exposure experiments. Band depletion immunoblotting revealed that 4-fold higher concentrations of extracellular TPT were required to induce the formation of topo I-DNA complexes in CHRC5 cells as compared to AuxB1 cells. To assess the role of Pgp in this resistance, drug accumulation and cytotoxicity assays were repeated in the absence and presence of quinidine. Addition of quinidine enhanced TPT accumulation (measured by high-performance liquid chromatography) and diminished the IC50 for TPT to a greater extent in CHRC5 cells than in AuxB1 cells. To examine whether similar effects could be detected in Pgp-expressing human cells, MCF-7/Adriar breast cancer cells and KG1a human acute myelogenous leukemia cells were examined. Quinidine or verapamil enhanced TPT accumulation in both of these cell lines but had no effect in parental MCF-7 cells or a variety of human leukemia cell lines that do not overexpress Pgp. Cytotoxicity measurements performed by counting the number of surviving cells (MCF-7/Adriar) or employing a modified, highly stable tetrazolium dye reduction assay (leukemia cell lines) revealed that quinidine diminished the IC50 for TPT in the Pgp-overexpressing cell lines but not in the control lines. These results suggest that Pgp overexpression diminishes TPT accumulation and TPT cytotoxicity in hamster and human cells. It should be stressed, however, that these effects were substantially smaller than the effects of Pgp overexpression on the accumulation and cytotoxicity of the anthracycline daunorubicin and the epipodophyllotoxin etoposide in the same cell lines.
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PMID:Effect of P-glycoprotein expression on the accumulation and cytotoxicity of topotecan (SK&F 104864), a new camptothecin analogue. 134 48

In a variety of adult and childhood leukaemia cell samples collected at different states of the disease, we analysed in a series of sequentially performed slot-blot or Northern-blot hybridisation experiments the expression of genes possibly involved in multiple drug resistance (MDR) (mdr1/P-glycoprotein, DNA topoisomerase II, glutathione-S-transferase pi), and the expression of the DNA topoisomerase I and histone 3.1 genes. Occasionally, P-glycoprotein gene expression was additionally examined by indirect immunocytofluorescence using the monoclonal antibody C219. No significant difference in mdr1/P-glycoprotein mRNA levels between primary and relapsed state acute lymphocytic leukaemias (ALL) was seen on average. Second or third relapses, however, showed a distinct tendency to an elevated expression of this multidrug transporter gene (up to 10-fold) in part well beyond the value seen in the moderately cross-resistant T-lymphoblastoid CCRF-CEM subline CCRF VCR 100. Increased mdr1/P-glycoprotein mRNA levels were also found in relapsed state acute myelogenous leukaemias (AML), and in chronic lymphocytic leukaemias (CLL) treated with chlorambucil and/or prednisone for several years. Topoisomerase I and topoisomerase II mRNA levels were found to be very variable. Whereas in all but one case of CLL topoisomerase II mRNA was not detected by slot-blot hybridizations, strong topoisomerase I and topoisomerase II gene expression levels, frequently exceeding the levels monitored in the CCRF-CEM cell line, were seen in many cell samples of acute leukaemia. If topoisomerase II mRNA was undetectable, expression of topoisomerase I was clearly visible throughout. These observations might be valuable considering the possible treatment with specific topoisomerase I or topoisomerase II inhibitors. Significant positive correlations were found (i) for topoisomerase I and histone 3.1 gene expression levels in general (P less than 0.001), and (ii) in the CLL samples additionally for the expression levels of the mdr1 gene, and the histone 3.1, topoisomerase I, and glutathione-S-transferase pi genes, respectively.
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PMID:Mdr1/P-glycoprotein, topoisomerase, and glutathione-S-transferase pi gene expression in primary and relapsed state adult and childhood leukaemias. 135 60

Topotecan (SK&F 104864), a water-soluble analogue of the topoisomerase I inhibitor camptothecin, is currently in Phase II clinical trial for solid tumors. We have characterized topotecan in terms of its effect upon gamma-radiation-induced cell killing. In colony formation experiments, subtoxic concentrations of topotecan (2 microM) potentiated radiation-induced killing of exponentially growing Chinese hamster ovary or P388 murine leukemia cultured cells. Survival curve shoulders were reduced; the slopes of the exponential portions of the curves were decreased to a small extent. D37 and D10 (radiation dose resulting in 37 and 10% survival of colony-forming ability) values were reduced by approximately 60 and 50%, respectively, in the case of Chinese hamster ovary cells. In P388 cells, topotecan reduced D37 by 35 to 40% and D10 by 20 to 25%. Potentiation of radiation-induced cell killing by topotecan was absolutely dependent upon the presence of the topoisomerase I inhibitor during the first few (less than 30) min after irradiation. Association of topoisomerase I with this effect was confirmed in studies of Chinese hamster ovary cells previously made resistant to camptothecin (and cross-resistant to topotecan), resulting in decreased cellular content of topoisomerase I. These cells were found to be 2- to 3-fold hypersensitive to gamma-radiation-induced killing. P388 camptothecin-resistant cells were further sensitized to the lethal effects of ionizing radiation by nontoxic treatment with the topoisomerase II inhibitor novobiocin, consistent with increased dependence of topoisomerase I-deficient cells upon topoisomerase II.
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PMID:Synergistic cell killing by ionizing radiation and topoisomerase I inhibitor topotecan (SK&F 104864). 165 71

Camptothecin, a specific inhibitor of topoisomerase I, caused erythroid differentiation of the human leukaemia cell-line K562, as assessed by benzidine staining at 70 h recovery following a 60 min treatment of the cells. Differentiation was confirmed by increased levels of epsilon-globin and gamma-globin mRNA in the treated cells and was accompanied by down-regulation of c-myb mRNA. Synchronisation of K562 cells by non-cytotoxic doses of methotrexate increased the differentiation induced by camptothecin, without affecting the camptothecin-induced inhibition of cellular proliferation. Camptothecin induction of differentiation and inhibition of proliferation may occur by independent mechanisms.
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PMID:Studies of the differentiation properties of camptothecin in the human leukaemic cells K562. 166 Feb 92

DNA topoisomerase inhibitors, camptothecin and 4'-demethylepipodophyllotoxin ethylidene-beta-D-glucoside (VP16) had strong differentiation-inducing activity for all five kinds of leukemia cells examined (human HL60, U937, ML1, and K562 cells and mouse M1 cells) as judged from measurements of various differentiation markers. The characteristics that appeared as a result of differentiation induced by these inhibitors were essentially similar in every cell line. Exposure to VP16 for 2 h induced both differentiation and DNA-strand breaks in K562 cells, whereas podophyllotoxin, which lacks topoisomerase II inhibitory activity, induced neither differentiation nor DNA-strand breaks in these cells. These results suggest a parallelism between the induction of differentiation and that of DNA-strand breaks. The combination of VP16 and recombinant tumor necrosis factor alpha (rTNF alpha) synergistically induced differentiation of human U937, ML1, and M1 cells and had an additive effect on HL60 cells. Simultaneous treatment with rTNF alpha plus camptothecin or VP16, or pretreatment with camptothecin or VP16, followed by rTNF alpha induced marked differentiation of M1 cells. These results indicate that inhibition of topoisomerase (either topoisomerase I or II) followed by the action of rTNF alpha was effective in inducing differentiation of leukemia cells.
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PMID:Topoisomerase inhibitors have potent differentiation-inducing activity for human and mouse myeloid leukemia cells. 184 45

Camptothecin (CPT), a plant alkaloid with antitumor activity, is a specific inhibitor of eukaryotic DNA topoisomerase I. We have previously isolated and characterized a CPT-resistant topoisomerase I isolated from a CPT-resistant human leukemia cell line, CPT-K5. cDNA clones of topoisomerase I were isolated from the CPT-resistant and the parental CPT-sensitive cell lines, respectively. Sequencing of the clones identified two mutations in the cDNA isolated from the resistant cells, which cause amino acid changes from aspartic acid to glycine at residues 533 and 583 of the parental topoisomerase I. When the CPT-K5 topoisomerase I was expressed in E. coli as a fusion protein with Staphylococcal Protein A fragment, the activity was resistant to CPT at a dose level up to 125 microM, whereas the parental fusion protein was sensitive to CPT as low as 1 microM. The resistance index (greater than 125) of the CPT-K5 fusion topoisomerase I is similar to that of the native CPT-K5 topoisomerase I. These results indicate that either or both of the two amino acid changes identified in the mutant enzyme is responsible for the resistance to CPT.
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PMID:Molecular cloning of a cDNA of a camptothecin-resistant human DNA topoisomerase I and identification of mutation sites. 184 60

Exposure of mouse lymphocytic L1210 cells to 0.02-0.5 micrograms/ml of camptothecin (CAM) causes a slowdown in the rate of cell progression through S and G2 phases of the cell cycle; the "terminal" point of CAM action is about 1 h prior to mitosis. Some cells also enter higher DNA ploidy and progress through the cycle at that ploidy. CAM exerts similar effects (S- and G2-phase arrest, entrance to higher DNA ploidy, low initial cytotoxicity) on human lymphocytic MOLT-4 leukemia cells. In contrast, treatment of human promyelocytic HL-60 cells with CAM results in the immediate (occurring as early as 2 h after treatment) death of S- and G2+M-phase cells; the dead cells exhibit decreased DNA stainability with intercalating dyes, suggestive of DNA degradation. Although CAM is less cytotoxic to another human myelogenous leukemic cell line, KG1, the latter cells also respond like HL-60, namely by selective death in S and G2. The data indicate that there may be a tissue (leukemia type) specificity in the response of cells to camptothecin and suggest that myelogenous leukemias, especially those characterized by high proliferation rates, may be especially sensitive to the cytotoxic action of this and perhaps other topoisomerase I inhibitors.
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PMID:Diverse effects of camptothecin, an inhibitor of topoisomerase I, on the cell cycle of lymphocytic (L1210, MOLT-4) and myelogenous (HL-60, KG1) leukemic cells. 216 79

Topoisomerase II has been suggested to have a role in the early events of differentiation. This possibility was evaluated by measuring the effects of inhibitors of topoisomerase II on the induction of the differentiation of WEHI-3B D+ monomyelocytic leukemia cells. Differentiation of this cell line was induced along the granulocytic pathway by treatment with the topoisomerase II inhibitors novobiocin (150-300 microM), teniposide (20-50 nM), etoposide (0.1 microM), elsamicin (0.5 microM), and doxorubicin (40 nM). Maturation was assessed by the morphological appearance of mature forms of the granulocytic lineage, an increase in cell surface Fc receptors, the ability to reduce nitroblue tetrazolium, and the loss of proliferative capacity. In contrast, the non-topoisomerase II-reactive agent cisplatin and the topoisomerase I-reactive drug camptothecin did not cause the maturation of WEHI-3B D+ cells. Aclacinomycin A and retinoic acid, which are known efficacious inducers of the differentiation of this cell line, affected topoisomerase II extracted from WEHI-3B D+ cells in vitro, causing concentration-dependent inhibition of the strand-passing activity of the enzyme. Treatment of WEHI-3B D+ cells with novobiocin at 150 microM for 3 h or with teniposide at 50 nM for 24 h resulted in a 2- to 3-fold increase in etoposide-induced protein-DNA cross-links. Nuclear proteins in 0.35 M NaCl extracts from cells treated with novobiocin at 150 microM for 3 h or with teniposide at 50 nM for 24 h showed a slight increase in topoisomerase II activity compared to untreated cells. No changes in topoisomerase II levels, as measured by immunoblotting, were detected after treatment of WEHI-3B D+ cells with 150 microM novobiocin or 50 nM teniposide during the first 2 days of treatment. At day 3 of treatment, however, a decrease in topoisomerase II was observed in cells treated with either drug, possibly due to decreased cellular proliferation consequent to cell differentiation. The findings support the conclusion that topoisomerase II may have a role in the induction of granulocytic differentiation of WEHI-3B D+ leukemia cells.
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PMID:Induction of the differentiation of WEHI-3B D+ monomyelocytic leukemia cells by inhibitors of topoisomerase II. 217 8


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