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

The partner gene of MLL was identified in a patient with treatment-related acute myeloid leukemia in which the karyotype suggested t(3;11)(q25;q23). Prior therapy included the DNA topoisomerase II inhibitors, teniposide and doxorubicin. Southern blot analysis indicated that the MLL gene was involved in the translocation. cDNA panhandle polymerase chain reaction (PCR) was used, which does not require partner gene-specific primers, to identify the chimeric transcript. Reverse-transcription of first-strand cDNAs with oligonucleotides containing known MLL sequence at the 5' ends and random hexamers at the 3' ends generated templates with an intra-strand loop for PCR. In-frame fusions of either MLL exon 7 or exon 8 with the GMPS (GUANOSINE 5'-MONOPHOSPHATE SYNTHETASE) gene from chromosome band 3q24 were detected. The fusion transcript was alternatively spliced. Guanosine monophosphate synthetase is essential for de novo purine synthesis. GMPS is the first partner gene of MLL on chromosome 3q and the first gene of this type in leukemia-associated translocations. (Blood. 2000;96:4360-4362)
 ...
PMID:t(3;11) translocation in treatment-related acute myeloid leukemia fuses MLL with the GMPS (GUANOSINE 5' MONOPHOSPHATE SYNTHETASE) gene. 1111 Jul 14

Chromosomal breakage resulting from stabilization of DNA topoisomerase II covalent complexes by epipodophyllotoxins may play a role in the genesis of leukemia-associated MLL gene translocations. We investigated whether etoposide catechol and quinone metabolites can damage the MLL breakpoint cluster region in a DNA topoisomerase II-dependent manner like the parent drug and the nature of the damage. Cleavage of two DNA substrates containing the normal homologues of five MLL intron 6 translocation breakpoints was examined in vitro upon incubation with human DNA topoisomerase IIalpha, ATP, and either etoposide, etoposide catechol, or etoposide quinone. Many of the same cleavage sites were induced by etoposide and by its metabolites, but several unique sites were induced by the metabolites. There was a preference for G(-1) among the unique sites, which differs from the parent drug. Cleavage at most sites was greater and more heat-stable in the presence of the metabolites compared to etoposide. The MLL translocation breakpoints contained within the substrates were near strong and/or stable cleavage sites. The metabolites induced more cleavage than etoposide at the same sites within a 40 bp double-stranded oligonucleotide containing two of the translocation breakpoints, confirming the results at a subset of the sites. Cleavage assays using the same oligonucleotide substrate in which guanines at several positions were replaced with N7-deaza guanines indicated that the N7 position of guanine is important in metabolite-induced cleavage, possibly suggesting N7-guanine alkylation by etoposide quinone. Not only etoposide, but also its metabolites, enhance DNA topoisomerase II cleavage near MLL translocation breakpoints in in vitro assays. It is possible that etoposide metabolites may be relevant to translocations.
 ...
PMID:Etoposide metabolites enhance DNA topoisomerase II cleavage near leukemia-associated MLL translocation breakpoints. 1117 Apr 41

The bisdioxopiperazines ICRF-187 (dexrazoxane), ICRF-193, and ICRF-154 are catalytic noncleavable complex-forming inhibitors of DNA topoisomerase II that do not produce protein-linked DNA strand breaks. In this study, we showed that bisdioxopiperazines induced erythroid differentiation, inhibited human leukemia K562 cell growth, and caused a slow induction of apoptosis. Dexrazoxane treatment caused DNA endoreduplication resulting in large highly polyploid cells. This result suggested the lack of a DNA topoisomerase II activity-based cell cycle checkpoint. The percentage of K562 cells that became apoptotic was much larger than the percentage of cells that stained for hemoglobin, suggesting that prior differentiation was not required for induction of apoptosis. Use of the Bcr-Abl tyrosine kinase inhibitor STI-571 resulted in a reduction in Bcl-xL levels and potentiation of dexrazoxane-induced apoptosis related to an earlier onset and more extensive cleavage of caspase-3. These results indicated that dexrazoxane-induced apoptosis is associated with a caspase-3 activation/cleavage pathway. In addition, these results were consistent with the antiapoptotic signaling function of Bcr-Abl to regulate expression of Bcl-xL. The ability of dexrazoxane to induce differentiation and apoptosis suggests that bisdioxopiperazines may be useful in treating some types of leukemia.
 ...
PMID:The catalytic DNA topoisomerase II inhibitor dexrazoxane (ICRF-187) induces differentiation and apoptosis in human leukemia K562 cells. 1117 39

The translocation t(11;16)(q23;p13) has only been documented in patients with acute leukemia or myelodysplasia secondary to therapy with drugs targeting DNA topoisomerase II. We have established a myeloid cell line (SN-1) with the MLL-CBP fusion gene from an acute leukemia patient with t(11;16)(q23;p13). Although SN-1 cells were not induced to differentiate by all-trans retinoic acid (ATRA) and 1alpha,25-dihydroxyvitamin D(3) (VD3), retinoid X receptor (RXR) agonists, such as 9-cis retinoic acid and Ro48-2250, effectively induced differentiation of the cells. Downregulation of the expression of the MLL-CBP fusion gene occurred during the differentiation of SN-1 cells. When SN-1 cells were treated with MLL-CBP antisense oligonucleotide, the cells were induced to differentiate by ATRA or VD3, suggesting that the MLL-CBP fusion gene dominant-negatively suppresses ATRA- or VD3-induced differentiation. Moreover, suboptimal concentrations of sodium butyrate, a histone deacetylase inhibitor, had a cooperative effect with ATRA or VD3 in inducing the differentiation of SN-1 cells. The downregulation of the expression of MLL-CBP mRNA was accompanied by the induction of differentiation. These findings suggest that RXR agonists or a clinically applicable combination of ATRA and butyrate derivatives might be useful for differentiation therapy in leukemia patients with the MLL-CBP fusion gene.
 ...
PMID:Downregulation of MLL-CBP fusion gene expression is associated with differentiation of SN-1 cells with t(11;16)(q23;p13). 1131 67

The epipodophyllotoxins etoposide and teniposide and other DNA topoisomerase II inhibitors including anthracyclines and dactinomycin are highly efficacious anticancer drugs. All are associated with a distinct form of leukemia characterized by chromosomal translocations as a treatment complication. Most of the translocations disrupt a breakpoint cluster region (bcr) of the MLL gene at chromosome band 11q23. Other characteristic translocations also may occur. The normal function of the nuclear enzyme DNA topoisomerase II is to catalyze changes in DNA topology between relaxed and supercoiled states by transiently cleaving and re-ligating both strands of the double helix. Anticancer drugs that are DNA topoisomerase II inhibitors are cytotoxic because they form complexes with DNA and DNA topoisomerase II. The complexes decrease the re-ligation rate, disrupt the cleavage-re-ligation equilibrium, and have a net effect of increasing cleavage. The increased cleavage damages the DNA and leads to chromosomal breakage. Cells with irreparable DNA damage die by apoptosis. The association of DNA topoisomerase II inhibitors with leukemia suggests that the drug-induced, DNA topoisomerase II-mediated chromosomal breakage may be relevant to translocations in addition to this anti-neoplastic, cytotoxic action. Epidemiological studies, genomic translocation breakpoint cloning and in vitro DNA topoisomerase II cleavage assays together lead to a model for treatment-related leukemia in which DNA topoisomerase II causes chromosomal breakage and translocations form when the breakage is repaired.
 ...
PMID:Leukemias related to treatment with DNA topoisomerase II inhibitors. 1134 Jun 7

The epipodophyllotoxin etoposide is a potent and widely used anticancer drug that targets DNA topoisomerase II. The synthesis, photochemical, and biological testing of a photoactivatable aromatic azido analogue of etoposide also containing an iodo group is described. This azido analogue should prove useful for identifying the etoposide interaction site on topoisomerase II. Irradiation of the azido analogue and an aldehyde-containing azido precursor with UV light produced changes in their UV--visible spectra that were consistent with photoactivation. The azido analogue strongly inhibited topoisomerase II and inhibited the growth of Chinese Hamster Ovary cells. Azido analogue-induced topoisomerase II--DNA covalent complexes were significantly increased subsequent to UV irradiation of drug-treated human leukemia K562 cells as compared to etoposide-treated cells. These results suggest that the photoactivated form of etoposide is a more effective topoisomerase II poison either by interacting directly with the enzyme or with DNA subsequent to topoisomerase II-mediated strand cleavage.
 ...
PMID:Synthesis and biological activity of a photoaffinity etoposide probe. 1142 78

The mixed lineage leukemia, MLL, gene is frequently rearranged in patients with secondary leukemia following treatment with DNA topoisomerase II inhibitors. By FISH and Southern blot analyses we identified a rearrangement in the MLL gene due to a novel t(3;11)(q28;q23) chromosomal translocation in a patient who developed AML-M5 3 years after treatment for a follicular lymphoma. Through inverse PCR, the LPP (lipoma preferred partner) gene on 3q28 was identified as the MLL fusion partner. LPP contains substantial identity to the focal adhesion protein, zyxin, and is frequently fused to HMGIC in lipomas. The breakpoint occurred in intron 8 of MLL and LPP. Two in-frame MLL-LPP transcripts, which fuse MLL exon 8 to LPP exon 9, were detected by RT-PCR, although the smaller of these contained a deletion of 120 bp from the MLL sequence. The predicted MLL-LPP fusion protein includes the A/T hook motifs and methyltransferase domain of MLL joined to the two last LIM domains of LPP. A reciprocal LPP-MLL transcript, predicted to include the proline-rich and leucine zipper motifs, and the first LIM domain of LPP were also detected by RT-PCR. In summary, LPP is a newly identified MLL fusion partner in secondary leukemia resulting from topoisomerase inhibitors. The MLL-LPP and LPP-MLL predicted proteins contain many of the features present in other MLL rearrangements.
 ...
PMID:Human LPP gene is fused to MLL in a secondary acute leukemia with a t(3;11) (q28;q23). 1143 29

We analyzed the der(11) and der(4) genomic breakpoint junctions of a t(4;11) in the leukemia of a patient previously administered etoposide and dactinomycin by molecular and biochemical approaches to gain insights about the translocation mechanism and the relevant drug exposure. The genomic breakpoint junctions were amplified by PCR. Cleavage of DNA substrates containing the normal homologues of the MLL and AF-4 translocation breakpoints was examined in vitro upon incubation with human DNA topoisomerase IIalpha and etoposide, etoposide catechol, etoposide quinone, or dactinomycin. The der(11) and der(4) genomic breakpoint junctions both involved MLL intron 6 and AF-4 intron 3. Recombination was precise at the sequence level except for the overall gain of a single templated nucleotide. The translocation breakpoints in MLL and AF-4 were DNA topoisomerase II cleavage sites. Etoposide and its metabolites, but not dactinomycin, enhanced cleavage at these sites. Assuming that DNA topoisomerase II was the mediator of the breakage, processing of the staggered nicks induced by DNA topoisomerase II, including exonucleolytic deletion and template-directed polymerization, would have been required before ligation of the ends to generate the observed genomic breakpoint junctions. These data are inconsistent with a translocation mechanism involving interchromosomal recombination by simple exchange of DNA topoisomerase II subunits and DNA-strand transfer; however, consistent with reciprocal DNA topoisomerase II cleavage events in MLL and AF-4 in which both breaks became stable, the DNA ends were processed and underwent ligation. Etoposide and/or its metabolites, but not dactinomycin, likely were the relevant exposures in this patient.
 ...
PMID:Near-precise interchromosomal recombination and functional DNA topoisomerase II cleavage sites at MLL and AF-4 genomic breakpoints in treatment-related acute lymphoblastic leukemia with t(4;11) translocation. 1149 4

An efficient five-step synthetic method was developed to access a series of spermine derivatives containing appended acridine, anthracene, and 7-chloroquinoline motifs. The derivatives were composed of a spermine fragment covalently tethered at its N4 and N9 positions to an aromatic nucleus via an aliphatic chain (e.g., 8: acridine -[C4 aliphatic tether]-spermine-[C4 aliphatic tether]-acridine). The distance separating the spermine and aromatic nuclei was altered via different tethers composed of four or five methylene units. These bis ligands (8, 9, 12, and 13) were shown to inhibit human DNA topoisomerase II (topo II) activity at 5 microM. Enzymatic activity was assessed as the ability to unknot (decatenate) and cleave kinetoplast DNA (kDNA). Polyamine conjugation did not disrupt the ability of the acridine-spermine conjugates 8 and 9 to inhibit topo II activity as compared with the 9-aminoacridine and 9-(N-butyl)aminoacridine controls (at 5 microM). The parent polyamines, spermine (5 microM) and spermidine (10 microM), had little effect on topo II activity. In general, the bis-substituted spermine derivatives (8, 9, 12, and 13) were more efficient topo II inhibitors at 5 microM than their monosubstituted spermidine counterparts (22-25) at 10 microM. Within the bisintercalator spermine series, insertion of an additional methylene unit (i.e., C5 tethers) increased potency 2-fold (8, bis-C4-acridine, 47 h IC(50) = 40 microM; 9, bis-C5-acridine, IC(50) = 17 microM). Comparison of the bis- and monoacridine spermine motifs (8 and 17) revealed a 4-fold increase in potency for the latter architecture (94 h IC(50) for 8, 74 microM; for 17, 17 microM). In general the bisintercalators (8, 9, 12, and 13) behaved as cytostatic agents, while the monosubstituted acridine and anthracene derivatives (22-25) were cytotoxic. Anthracene-containing conjugates were generally more toxic than their acridine counterparts in an L1210 (murine leukemia) cell assay. Of the conjugates tested the (monointercalator)-spermine motif (e.g., 17) had the highest affinity for the L1210 polyamine transporter as revealed by spermidine protection experiments.
 ...
PMID:Influence of polyamine architecture on the transport and topoisomerase II inhibitory properties of polyamine DNA-intercalator conjugates. 1160 33

Topoisomerase II represents the main target for the antitumour drugs etoposide and amsacrine, which are both used clinically. Previous studies have shown that the glycoside moiety of etoposide is not necessary for cytotoxicity or DNA topoisomerase II inhibition. For this reason, we designed two epipodophyllotoxin derivatives for which the dispensable sugar moiety of etoposide has been replaced by a m-methoxy-methane-sulfonamide-anilino group analogous to the topoisomerase II-targeted domain of amsacrine. We report the synthesis of the hybrid molecules that have the epipodophyllotoxin and anilino groups directly linked (ICP-114) or connected by an ethylene spacer (ICP-147). Plasmid DNA relaxation and kinetoplast DNA decatenation assays were used to evaluate the effects of the drug on the catalytic activity of human topoisomerase II. We found that the hybrid ICP-147 was significantly more potent than both etoposide and amsacrine at stimulating DNA cleavage by the enzyme, whereas the hybrid ICP-114 lacking the linker chain was less potent. ICP-147 produces approximately 3 times more double-stranded breaks than ICP-114, suggesting that an ethylene spacer between the epipodophyllotoxin and amsacrine moieties is highly effective at inhibiting topoisomerase II. Sequencing data also supported the idea that the two moieties of ICP-147 participate to the interaction with topoisomerase II-DNA covalent complexes. Both hybrid compounds are more cytotoxic than etoposide but much less toxic than amsacrine toward L1210 leukemia cells. In addition to its effect on topoisomerase II, ICP-114 can inhibit tubulin polymerization, whereas ICP-147 is almost totally inactive in this assay. The unexpected capacity of ICP-114 to interfere with the polymerization of tubulin suggests that this compound can target tubulin dimers, as it is the case with certain antitumor sulfonamides. The design of etoposide-amsacrine hybrids may thus represent an opportunity for the discovery of dual inhibitors that target both topoisomerase II and tubulin.
 ...
PMID:Design of two etoposide-amsacrine conjugates: topoisomerase II and tubuline polymerization inhibition and relation to cytotoxicity. 1171 34


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>