UMLS:C0023418 - FACTA Search

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Query: UMLS:C0023418 (leukemia)
93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To search for possible synergy between topoisomerase (topo) II-directed chemotherapeutic agents and topo I-directed agents, IL-60 human progranulocytic leukemia cells were incubated with etoposide in the absence or presence of camptothecin (CPT). Treatment of HL-60 cells for 1 h with 15-20 microM etoposide resulted in the death of 99-99.9% of the cells as assessed by colony formation in soft agar. Unexpectedly, simultaneous incubation with 1 microM CPT increased the survival of etoposide-treated cells as much as 30-fold. Inhibition of etoposide cytotoxicity was observed at CPT concentrations as low as 0.01 microM and was one-half maximal at 0.1 microM. CPT also antagonized the cytotoxicity of 4'-(9-acridinylamino)methanesulfon-M-anisidide and daunorubicin, two structurally unrelated topo II-directed agents. Topotecan, a CPT analogue currently undergoing Phase I clinical trials, had a similar effect. Studies using an alkaline unwinding assay (to measure DNA strand breaks) and Western blotting (to assess formation of covalent adducts involving topo II) revealed that CPT did not alter the ability of etoposide to stabilize topo II-DNA adducts. CPT is a potent inhibitor of both DNA and RNA synthesis. To further assess the mechanism by which CPT diminished the cytotoxicity of topo II-directed agents, inhibitors of DNA synthesis or RNA synthesis were substituted for CPT. Aphidicolin, an inhibitor of replicative DNA polymerases, enhanced the survival of etoposide-treated HL-60 cells less than 3-fold. In contrast, inhibitors of RNA synthesis (cordycepin or 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole) enhanced the survival of etoposide-treated HL-60 cells as much as 20-fold. The potential biological and therapeutic implications of these results are discussed.
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PMID:Antagonism between camptothecin and topoisomerase II-directed chemotherapeutic agents in a human leukemia cell line. 170 67

Among the cytostatic drugs only the alkylating agents have been firmly established as being leukaemogenic. This report describes 4 cases of acute myeloid leukaemia and 1 of myelodysplasia occurring in a cohort of 212 patients with germ-cell tumours treated with etoposide, cisplatin, and bleomycin. The mean cumulative risk of leukaemic complications was 4.7% (SE 2.3) 5.7 years after start of etoposide-containing chemotherapy, and, compared with the risk in the general population, the relative risk of overt leukaemia was 336 (95% CI 92-861). No leukaemias were detected in a previous cohort of 127 patients with germ-cell tumours treated with cisplatin, bleomycin, and vinblastine. The increased risk of leukaemia was most probably due to etoposide alone or in combination with cisplatin or bleomycin, since other published work has also not revealed an excess of leukaemias among patients with germ-cell tumours treated with only cisplatin, bleomycin, and vinblastine. The risk of leukaemia was dose related since all 5 patients with leukaemic complications were among the 82 who had received a cumulative dose of more than 2000 mg/m2 etoposide, whereas no leukaemias were observed among 130 patients who had received up to 2000 mg/m2 (p = 0.004). 3 of the leukaemic patients had balanced chromosome translocations affecting bands 11q23 and 21q22. These translocations, and perhaps also other balanced aberrations, seem to be characteristic of myelodysplasia and acute leukaemia occurring after therapy with cytostatic agents acting on DNA-topoisomerase II.
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PMID:Increased risk of myelodysplasia and leukaemia after etoposide, cisplatin, and bleomycin for germ-cell tumours. 168 78

Cytotoxic effects and topoisomerase II-mediated DNA breaks induced in vitro by ellipticine derivatives were examined in connection with 1H NMR and circular dichroism (CD) studies on molecular structures and interactions of drugs with DNA. The compounds included four 9-hydroxyellipticine and two 7-hydroxyisoellipticine derivatives. Structure-activity relationships indicated that a change in nitrogen atom position in the pyridinic ring greatly affected drug effects both on topoisomerase II action and cytotoxicity to L1210 cells. The four 9-hydroxyellipticine derivatives yielded bell-shaped curves in in vitro topoisomerase II-mediated DNA break assays, whereas the two 7-hydroxyisoellipticine derivatives demonstrated an almost linear increase at the same concentration (0-10 microM). In both cases, the intensity of cleavage was modulated by the position and the degree of methylation on the pyridinic ring, and results were correlated with cytotoxic activity expressed as the in vitro ID50 values for L1210 leukemia cells. 1H NMR experiments performed on free drug molecules in solution revealed that the two protons (alpha and beta) contiguous to the biologically important hydroxy group were sensitive to changes in electron distribution produced by the distant chemical modifications and methylations of the pyridinic ring. A linear relationship was observed between the differences in chemical shifts of alpha and beta protons (delta delta alpha-beta) versus ID50 values. CD experiments indicated that, at weak ionic strength I = 0.02 and at pH 7, drugs interact with the poly[d(A-T)] duplex according to a "three-mode binding model" which is governed by the drug structure and the drug to DNA ratio. The intercalation mode was related to the induction of topoisomerase II-mediated DNA cleavage, while the external binding mode consecutive to intercalation was related to cleavage suppression. These two modes concerned the good intercalators 9-hydroxyellipticines. The third was found for the weak intercalators 7-hydroxyisoellipticines and was characterized by self-stacked molecules bound "outside" DNA, presumably in the minor groove. Ligands either could be intercalated partially or linked at the edge of bases with a small number of molecules filling intercalation sites, for the second alternative. In addition to having different binding modes, 9-hydroxyellipticines were better inducers of DNA distortions than 7-hydroxyisoellipticines. The incidence of the drug binding modes on DNA-topoisomerase II recognition was discussed in connection with the in vitro cytotoxic activity exhibited by the drugs.
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PMID:DNA-drug recognition and effects on topoisomerase II-mediated cytotoxicity. A three-mode binding model for ellipticine derivatives. 184 65

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

The administration of the DNA topoisomerase II inhibitors 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA) (10(-7) M), VP-16 (2 x 10(-7) M), or novobiocin (1.5 x 10(-4) M) reduces the growth activity of human promonocytic leukemia U-937 cells, by arresting them preferentially at the G2 (m-AMSA and VP-16) or at the G1 and G2 (novobiocin) phases of the cell cycle. Under these conditions, m-AMSA and VP-16 induce the differentiation of the cells efficiently, as proved both by an increase in the production of reactive oxygen species and by the activation of the surface expression of CD11b and CD11c, two differentiation-specific antigens. Novobiocin also induces the expression of those differentiation markers, but to a lesser extent. Analyses by Northern blot indicate that the topoisomerase II inhibitors reduce the levels of c-myc and beta-actin mRNA and increase the levels of vimentin mRNA. The expression of vimentin is also stimulated at the protein level, as indicated by immunofluorescence assays. This represents one of the few known instances in which topoisomerase inhibitors stimulate gene expression in eukaryotic cells.
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PMID:Differentiation of human promonocytic leukemia U-937 cells with DNA topoisomerase II inhibitors: induction of vimentin gene expression. 185 89

HL-60/AMSA is a human leukemia cell line that is 50-100-fold more resistant than its drug-sensitive HL-60 parent line to the cytotoxic actions of the DNA intercalator amsacrine (m-AMSA). HL-60/AMSA topoisomerase II is also resistant to the inhibitory actions of m-AMSA. HL-60/AMSA cells and topoisomerase II are cross-resistant to anthracycline and ellipticine intercalators but relatively sensitive to the nonintercalating topoisomerase II reactive epipodophyllotoxin etoposide. We now demonstrate that HL-60/AMSA and its topoisomerase II are cross-resistant to the DNA intercalators mitoxantrone and amonafide, thus strongly indicating that HL-60/AMSA and its topoisomerase II are resistant to topoisomerase II reactive intercalators but not to nonintercalators. At high concentrations, mitoxantrone and amonafide were also found to inhibit their own, m-AMSA's, and etoposide's abilities to stabilize topoisomerase II-DNA complexes. This appears to be due to the ability of these concentrations of mitoxantrone and amonafide to inhibit topoisomerase II mediated DNA strand passage at a point in the topoisomerization cycle prior to the acquisition of the enzyme-DNA configuration that yields DNA cleavage and topoisomerase II-DNA cross-links. In addition, amonafide can inhibit the cytotoxic actions of m-AMSA and etoposide. Taken together, these results suggest that the cytotoxicity of m-AMSA and etoposide is initiated primarily by the stabilization of the topoisomerase II-DNA complex. Other topoisomerase II reactive drugs may inhibit the enzyme at other steps in the topoisomerization cycle, particularly at elevated concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cross-resistance of an amsacrine-resistant human leukemia line to topoisomerase II reactive DNA intercalating agents. Evidence for two topoisomerase II directed drug actions. 185 Feb 98

The in vitro effects of the 2-(arylmethylamino)-1,3-propanediols (AMAPs) on macromolecular synthesis have been examined using the murine leukemia, P388, and the human mammary adenocarcinoma, MCF-7, under conditions of short-term drug exposure. AMAPs that were observed to inhibit macromolecular synthesis produced nearly equipotent inhibition of DNA and RNA synthesis. Equivalent inhibition of protein synthesis generally required significantly greater concentrations of AMAP. There is a general correlation between inhibition of polynucleotide synthesis and in vivo antitumor activity. The effects of four clinical candidate AMAPs (crisnatol, 773U82, 502U83, and 7U85) on macromolecular synthesis were further compared with those of actinomycin D, doxorubicin, mitoxantrone, etoposide, amsacrine, and cisplatin in MCF-7 cells. The pattern of AMAP action was most similar to that observed for doxorubicin and mitoxantrone. Finally, the effects of these four AMAPs on the size, specific activity, and rate of incorporation of [3H]-dTTP into DNA of MCF-7 cells synchronized by pretreatment with hydroxyurea was determined. It was found that DNA synthesis was inhibited by AMAPs independent of inhibition of the uptake, phosphorylation, or retention of the metabolic precursors. These results support the theory that antitumor AMAPs interfere with the normal functioning of enzymes, such as topoisomerase II or DNA and RNA polymerases, which interact with DNA.
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PMID:Effects of isomeric 2-(arylmethylamino)-1,3-propanediols (AMAPs) and clinically established agents on macromolecular synthesis in P388 and MCF-7 cells. 187 97

Enhanced DNA repair has been identified as a major mechanism of resistance to the anticancer drug cisplatin in murine leukemia L1210 cells. Studies of other cells have implicated the elevation of a variety of RNA transcripts in cisplatin resistance. This study investigated potential changes in transcription of these genes as well as genes involved in DNA repair. No elevation in any of the following transcripts was observed: thymidylate synthase, dihydrofolate reductase, DNA polymerase alpha, DNA polymerase beta, topoisomerase II, Ha-ras, beta-tubulin, metallothionein and the DNA repair genes ERCC1 and ERCC2. Thymidine kinase was increased no more than 2-fold. None of these RNA were induced by incubation with cisplatin. High levels of cisplatin produced selective decreases in certain RNA. These results demonstrate that the previous observations of elevated RNA can not be universally applied to all cisplatin-resistant cells.
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PMID:Analysis of various mRNA potentially involved in cisplatin resistance of murine leukemia L1210 cells. 197 66

In previous studies we used Southern blotting to examine the topoisomerase II locus (on chromosome 17) in human leukemia cell lines and noted a difference in the XmnI restriction endonuclease digestion pattern between an m-AMSA-resistant line and its m-AMSA-sensitive parent line (Zwelling, L. A.; Hinds, M,; Chan, D.; Mayes, J.; Sie, K. L.; Parker, E.; Silberman, L.; Radcliffe, A.; Beran, M.; Blick, M. Characterization of an amsacrine-resistant line of human leukemia cells. Evidence for a drug-resistant form of topoisomerase II. Journal of Biological Chemistry 264:16411-16420; 1989). We now demonstrate that the variable XmnI digestion pattern represents a normal restriction fragment length polymorphism (RFLP) which is observed in subjects without malignant disease and exhibits an autosomal pattern of inheritance. These data suggest that the previously described deviation in the genomic structure of topoisomerase II in the m-AMSA-resistant cell line did not reflect a new mutation, but rather a reduction to homozygosity at the topoisomerase II locus. This reduction to homozygosity is not due to chromosomal loss, as chromosome 17-specific gene probes clearly identify two chromosome 17's in the sensitive line and four in the resistant line, using chromosome painting with a chromosome 17-specific library. Some other genetic change must be the cause of the resistance of HL-60/AMSA and its topoisomerase II to the inhibiting actions of m-AMSA.
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PMID:A restriction fragment length polymorphism for human topoisomerase II: possible relationship to drug-resistance. 197 87

Murine leukemia L1210 cells selected for progressive resistance to doxorubicin (DOX) display both the multidrug resistant (MDR) phenotype and reductions in drug induced topoisomerase II-mediated DNA cleavage in nuclear extracts (Ganapathi, R.; Grabowski, D.; Ford, J.; Heiss, C.; Kerrigan, D.; Pommier, Y., Cancer Commun. 1:217-224; 1989). The present study was performed to characterize the results of exposure of the sensitive (S) and progressively DOX-resistant (10-fold, R1, and 40-fold, R2) L1210 cells to the topoisomerase II inhibitor, etoposide, and to investigate the modulating effects of the calmodulin inhibitor, trifluoperazine (TFP). Immunoblotting experiments indicated no apparent decrease in the p170 or p180 isoforms of topoisomerase II in the resistant sublines versus parental sensitive cells. Cross-resistance to etoposide (VP-16) was similar to that of DOX (10- and 40-fold). A non-cytotoxic concentration of 5 microM TFP enhanced cell kill 1.5- fold in the sensitive and 3- to 5-fold in the progressively DOX-resistant cells. Accumulation of VP-16 was 30% to 50% lower in the resistant sublines versus similarly treated sensitive cells, and a marked enhancement of drug uptake in the presence of TFP was observed in the sensitive but not in the resistant cells exposed to equivalent extracellular levels of VP-16. Although equimolar concentrations of VP-16 produced fewer DNA single strand breaks (SSB) and DNA protein crosslinks (DPC) in the resistant versus sensitive cells, similar DNA damage was apparent when S and R1, but not R2, cells were treated at VP-16 concentrations that produced equivalent cell death.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Trifluoperazine modulation of resistance to the topoisomerase II inhibitor etoposide in doxorubicin resistant L1210 murine leukemia cells. 199 27

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