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)

A human HL-60 leukemia cell line selected for resistance to mitoxantrone, HL-60/MX2, displays cross-resistance only to agents whose cytotoxicities result from interaction with the nuclear enzyme DNA topoisomerase II (topo II). The topo II catalytic activity is reduced 2-fold in the drug-resistant cell line in association with the absence of the M(r) 180,000 isoform of topo II and the finding of novel M(r) 160,000 topo II alpha-related immunoreactive protein in these cells by immunoblot. The topo II alpha (M(r) 170,000) protein levels in nuclear extracts from the HL-60/MX2 cells were noted on average to be approximately 40% lower than in comparable HL-60 nuclei. Studies of the subcellular localization of topo II by immunohistochemical and fractional extraction techniques demonstrated that the M(r) 160,000 topo II alpha-related protein is primarily localized in the cytoplasm. Levels of the 6.3-kilobase topo II alpha mRNA were noted to be reduced 2-fold in the HL-60/MX2 cells in association with the finding of a novel 4.8-kilobase topo II alpha-related mRNA transcript that was present in HL-60/MX2 but not HL-60 cells. The absence of topo II beta protein in nuclear and whole cell extracts from the HL-60/MX2 cells was associated with the virtual absence of detectable topo II beta mRNA in those cells by Northern blot analysis. Using a reverse transcription-PCR assay we were able to demonstrate the presence of very low levels of topo II beta mRNA in HL-60/MX2 cells, representing < 1% of that found in the HL-60 cells. In contrast, the nuclear catalytic activity and cellular mRNA levels of the related nuclear enzyme DNA topoisomerase I were nearly identical in the two cell types. Southern blot analysis of DNA extracted from the drug-sensitive and drug-resistant cells revealed a structural alteration in one topo II alpha allele in the HL-60/MX2 cells, but there was no evidence of rearrangement or hypermethylation of the topo II beta locus. These results indicate that the reduced levels of topo II alpha and beta isoenzymes observed in mitoxantrone-resistant HL-60/MX2 cells are related to changes in the levels of their respective mRNA transcripts. The identification of structural changes in one topo II alpha allele in the HL-60/MX2 cell line suggests that the altered allele may serve as the source of the unique 4.8-kilobase topo II alpha-related mRNA transcript and the M(r) 160,000 protein discovered in those cells.
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PMID:Alterations in the topoisomerase II alpha gene, messenger RNA, and subcellular protein distribution as well as reduced expression of the DNA topoisomerase II beta enzyme in a mitoxantrone-resistant HL-60 human leukemia cell line. 771 79

The cytotoxic efficacy of antitumor drugs targeted at DNA topoisomerase II (topo II) in many cases varies in direct proportion to cellular topo II content. To investigate the transcriptional control of the predominant alpha form of topo II, the 5' flanking region of the human topo II alpha gene (positions -562 to +90) was subcloned into a firefly luciferase reporter plasmid and transiently transfected into HL-60 human leukemia cells, a line capable of monocytic differentiation after treatment with various agents. Early in phorbol-12-myristate-13-acetate (30 nM)-induced differentiation (18-24 hr after treatment), an unexpected 3-5-fold activation of topo II alpha gene promoter activity was observed. Activation was observed in HL-60 cells and U-937 cells, but not in HeLa human cervical carcinoma cells. Sodium butyrate (NaB) (0.4 mM) also led to activation (4-17-fold) of the topo II alpha promoter in HL-60 and U-937 cells. Promoter sequences between position -90 and position +90 mediated the inducing effects of NaB. This NaB-dependent promoter-reporter induction was partly mirrored by a transient approximately 2-fold increase in endogenous topo II alpha enzyme. The stimulus for promoter activation could be partly attributed to a 2-fold increase in DNA synthesis at 16 hr for NaB, but not phorbol-12-myristate-13-acetate. Regardless of the primary stimulus for topo II alpha promoter trans-activation, it could be bypassed by treatment of HL-60 cells with NaB for 48 hr before transfection, revealing the expected 60-70% suppression of topo II alpha promoter activity. Further study of topo II alpha promoter down-regulation later in monocytic differentiation may serve as a model for elucidating the transcriptional mechanisms that may also be exploited by tumor cells expressing intrinsic or acquired resistance to topo II-directed drugs.
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PMID:Topoisomerase II alpha promoter trans-activation early in monocytic differentiation of HL-60 human leukemia cells. 772 30

A growth factor-dependent cell line (TF-1) was treated with interleukin-3 (IL-3) or medium in combination with variable doses of VP-16 to test whether the latter's cytotoxicity can be modulated by IL-3. The results demonstrated that an augmented cell death occurred with TF-1 cells when pre-incubated for 24 h with IL-3 followed by treatment with VP-16 (10 micrograms/ml) for 1 h. The increased cell death could not be ascribed to an increased number of apoptotic cells as measured with the acridine orange method. However, the IL-3 treatment coincided with an upregulation of DNA topoisomerase II alpha (Topo II alpha) at mRNA and protein level after 24 h, which was preceded by an upregulation of c-myc mRNA. In contrast, Topo II beta did not demonstrate an upregulation at mRNA level in response to IL-3 stimulation. In addition, it was shown that cells treated with IL-3 followed by VP-16 demonstrated a higher number of cleavable DNA complexes which was not due to an increased uptake of VP-16, since cellular concentrations of VP-16 in the presence of IL-3 or medium were 16.8 +/- 7.8 ng/10(6) cells and 19.8 +/- 7.8 ng/10(6) cells (mean +/- SD, n = 3), respectively. These data indicate that IL-3 pretreatment followed by VP-16 results in an increased cell death due to cytotoxicity which may be ascribed to an upregulation of Topo II alpha.
Leukemia 1994 Dec
PMID:VP-16-mediated cytotoxicity is modulated by interleukin-3 in a growth factor-dependent leukemic cell line. 780 95

Acute leukaemia, both myeloid and lymphoblastic, in patients treated for Hodgkin's disease (HD) is thought to have a poor prognosis. We report four adults who developed secondary acute lymphoblastic leukaemia (ALL) following chemoradiotherapy for HD. The chromosomal translocation t(4;11) (q21;q23) was found in two patients who received a chemotherapeutic regimen containing the DNA topoisomerase II inhibitor etoposide. Three of the four patients are alive and in unmaintained first remission at 3, 5 and 9 years from diagnosis of ALL, two following autologous bone marrow transplantation. These results suggest that ALL following HD may have a good prognosis when treated aggressively.
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PMID:Acute lymphoblastic leukaemia following Hodgkin's disease is associated with a good prognosis. 791 85

cis-Dichlorodiammineplatinum(II) (CDDP) resistance in L1210/10 murine leukemia cells is multifactorial and involves decreased drug uptake, increased glutathione content, and enhanced DNA repair activity. We show here that 0.35 M NaCl nuclear extracts from L1210/10 cells possess an approximately 3-fold increase in DNA topoisomerase II activity, compared with parental L1210 cells, as measured by decatenation of kinetoplast DNA. No difference in topoisomerase I activity is observed between the two cell lines. Immunoblot analysis of topoisomerase II protein in resistant and sensitive cells suggests that the observed differences in topoisomerase II activity cannot be explained by differences in the level of protein expressed. L1210/10 cells are 2.5-fold more sensitive than L1210 cells to the cytotoxic effects of the topoisomerase II inhibitor 4'-(9-acridylamino)methane-sulfon-m-anisidide. Sequential treatment with 4'-(9-acridyl-amino)methanesulfon-m-anisidide and CDDP leads to an additive cytotoxic effect of the two drugs in sensitive L1210 cells, as determined by colony formation in semi-solid medium. In contrast, the same treatment leads to a supra-additive effect in L1210/10 cells, which strongly suggests a role for topoisomerase II in the CDDP resistance of this cell line.
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PMID:A cisplatin-resistant murine leukemia cell line exhibits increased topoisomerase II activity. 793 22

Etoposide (VP-16) is one of several DNA-damaging agents that induce subcellular structural changes associated with apoptosis. VP-16 exerts its DNA-damaging and cytotoxic effects subsequent to interference with DNA topoisomerase II activity. VP-16 also stimulates c-jun and c-fos mRNA expression in some cell lines, including human leukemia K562 and HL-60 cells. To compare the temporal relationship between drug-induced c-jun expression and apoptosis, we examined cell morphology, cell viability, DNA integrity, and c-jun induction during VP-16 treatment of K562 and HL-60 cells. VP-16 (10 microM)-induced internucleosomal DNA damage and nuclear fragmentation were readily apparent within 6 hr in HL-60 cells but were absent in K562 cells treated for up to 24 hr. Some internucleosomal DNA damage was observed in K562 cells but only after treatment with 100 microM VP-16 for 24 hr. In contrast, VP-16-induced DNA single-strand breaks, VP-16-induced topoisomerase II/DNA covalent complex formation, and VP-16-mediated growth inhibition were similar in K562 and HL-60 cells. Also, the time course of VP-16-induced c-jun mRNA expression was comparable for both K562 and HL-60 cell lines. Western blot analysis of whole-cell lysates showed that Bcl-2 protein levels were 13-fold greater in HL-60 cells than in K562 cells. Thus, the resistance of VP-16-treated K562 cells to apoptosis was not attributable to protection by Bcl-2. Furthermore, the relatively high levels of Bcl-2 in HL-60 cells were not sufficient to protect these cells against apoptosis. Together, our results indicate that the temporal coupling of VP-16-induced DNA damage, c-jun expression, and apoptosis is cell type specific and suggest that different signaling pathways for apoptosis are operating in these two human leukemia cell lines.
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PMID:Differential induction of etoposide-mediated apoptosis in human leukemia HL-60 and K562 cells. 796 39

We report three patients with acute promyelocytic leukaemia (APL) occurring after treatment for other malignant disorders. One patient had had razoxane (a drug affecting DNA topoisomerase II) for cancer of the colon, and the other two had had treatment for cancer of the breast. Two out of the three patients went into complete remission. We review the published literature on therapy-related acute promyelocytic leukaemia (t-APL) and suggest that it is a genuine clinical entity which may be caused by drugs affecting DNA topoisomerase II, and has a prognosis similar to de novo APL.
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PMID:Therapy-related acute promyelocytic leukaemia. 794 1

A series of 9-anilinoacridines, based on the anticancer drug amsacrine [4'-(9-acridinylamino)methanesulphon-m-anisidide; m-AMSA], were synthesized and evaluated for their ability to inhibit both the growth of Jurkat leukaemia cells and human DNA topoisomerase II in vitro. Inhibition of topoisomerase II activity occurred via one of two mechanisms of drug action: (i) direct inhibition of the strand-passing activity or (ii) stabilization of cleavable complex formation. Although the majority of compounds evaluated inhibited P4 DNA unknotting activity catalysed by DNA topoisomerase II up to 100 microM, derivatives bearing 1'-substituents containing SO2 moieties (e.g. 1'-NHSO2Me and 1'-SO2NH2 groups) were generally the most potent inhibitors of DNA topoisomerase II-mediated DNA religation, being effective at concentrations of 1-5 microM. No obvious correlation was observed between the cytotoxicity of individual drugs and linear DNA formation in the in vitro topoisomerase II assays, either across the whole drug series or within similar subgroups. However, a selected group of drugs with different cytotoxicities (compounds 5, 12 and 30; Table I) stimulated DNA topoisomerase II-mediated DNA strand breaks in intact Jurkat cells by 3.5-, 11- and 2.2-fold, respectively, at a concentration of 10 microM, while compounds 31 and 32 did not produce protein-associated DNA strand breaks in whole cells. There was a good correlation between the ability of these selected compounds to induce topoisomerase II-mediated DNA strand breaks in vitro or in whole cells, and their cytotoxicity to Jurkat cells.
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PMID:Structure-activity relationships of 9-anilinoacridines as inhibitors of human DNA topoisomerase II. 803 52

Previous studies using cloned lines of Adriamycin-sensitive and -resistant P388 murine leukemia cells have suggested that a reduction in DNA topoisomerase II alpha (topo II alpha) enzyme activity and protein levels in drug-resistant cell lines (A. M. Deffie, J. K. Batra, and G. J. Goldenberg, Cancer Res., 49: 58-62, 1989) may be due to an allelic mutation in the topo II alpha gene (A. M. Deffie, D. J. Bosman, and G. J. Goldenberg, Cancer Res., 49: 6879-6882, 1989). The drug-resistant cell lines P388/ADR/3 and P388/ADR/7 express a shortened topo II alpha mRNA transcript in addition to the native transcript present in the drug-sensitive P388/4 cell line. Using complementary DNA probes derived from the coding sequence and 3' untranslated region of the native mouse topo II alpha transcript, we have determined that the shorter 4.5-kilobase topo II alpha transcript expressed in the drug-resistant cell lines contains only 3.5-kilobases of topo II sequence from the 5'-terminus onwards. Using a 3'-rapid amplification of cDNA ends strategy, we have cloned cDNAs representing the 3'-termini of both the native and mutant transcripts from both P388/ADR/3 and P388/ADR/7 cells. DNA sequence analysis revealed that the shorter 4.5-kilobase transcript: (a) encodes topoisomerase II alpha until nucleotide position 3494, at which point the sequence diverges for the remaining 956 bases; (b) contains a polyadenylation signal distinct from the native transcript; and (c) contains an open reading frame predicting a truncated topo II alpha fusion protein. Of great interest was the finding that the non-topo II alpha 956-base sequence in the shorter transcript encodes the promoter, exon I, and part of the first intron of the murine retinoic acid receptor alpha gene locus in the antisense orientation, suggesting that a rearrangement on chromosome 11 in the drug-resistant cells led to a gene fusion event between the loci encoding topo II alpha and retinoic acid receptor alpha.
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PMID:Characterization of a DNA topoisomerase IIalpha gene rearrangement in adriamycin-resistant P388 leukemia: expression of a fusion messenger RNA transcript encoding topoisomerase IIalpha and the retinoic acid receptor alpha locus. 826 98

Sublines of K562 human leukemia cells were selected for resistance (30- to 80-fold) to etoposide by continuous exposure to 0.5 microM VP-16. Two etoposide-resistant cell lines, K/VP.5 and K/VP.5-1, showed a 5-fold reduction in levels of topoisomerase II alpha protein compared with K562 cells. Northern analysis indicated a 2.5-fold reduction in topoisomerase II alpha mRNA in etoposide-resistant cell lines, due in part to a 1.7-fold decrease in topoisomerase II mRNA stability with no change in transcription rate. Immunoblotting assays of electrophoresed cell lysates from VP-16-treated cells revealed less drug-induced covalent topoisomerase II/DNA adducts in resistant than in sensitive cells, suggesting a functional alteration in resistant cell topoisomerase II. Recent reports of specific topoisomerase II DNA binding sites near the promoter sites of growth response genes and alterations of gene expression in cells treated with topoisomerase II inhibitory drugs led to experiments to determine if the apparent functional alterations of topoisomerase II were accompanied by changes in the regulation of these genes. Therefore, the expression of several growth response genes was compared by northern analysis in parental K562 and both VP-16-resistant cell lines. Basal levels of c-myc were comparable for all three cell lines, but levels of c-jun and c-fos were elevated 2- to 4-fold in VP-16-resistant cell lines. Increased levels of c-fos and c-jun were not a result of altered rates of transcription, as determined by nuclear run-off assays. Exposure of both sensitive and resistant cells to 200 microM VP-16 for 5 hr resulted in no further changes in topoisomerase II mRNA levels but caused an additional 2- to 3-fold elevation in the level of c-jun mRNA, indicating that altered basal levels of this gene were not due to deregulation of this gene. Acquired VP-16 resistance in K/VP.5 and K/VP.5-1 cells was accompanied by reduced levels and altered activities of DNA topoisomerase II as well as changes affecting the expression of genes important for growth and differentiation.
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PMID:Altered gene expression in human leukemia K562 cells selected for resistance to etoposide. 826 50


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