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)

Cloning and sequencing of cDNA segments of human TOP2 gene encoding the 170 kDa form of human DNA topoisomerase II show that Arg486 of the enzyme has been mutated to a lysine in the enzyme from two human leukemia cell lines HL-60/AMSA and KBM-3/AMSA, which were independently selected for resistance to the antitumor drug amsacrine (4'-[9-acridinylamino]-methanesulfon-m-anisidide, mAMSA). Sequence identity comparisons between eukaryotic DNA topoisomerase II and bacterial gyrase (bacterial DNA topoisomerase II) indicate that the position of the common mutation observed in mAMSA-resistant human TOP2 corresponds to that of the point mutation nal-31 in the Escherichia coli gyrase B gene, which confers resistance to nalidixic acid. Because mAMSA and nalidixic acid are known to act on their respective targets by a common mechanism of trapping the covalent enzyme-DNA intermediates, these results provide strong evidence that the 170 kDa form of human DNA topoisomerase II is a major cellular target of mAMSA, and that Arg486 of this enzyme is involved in mAMSA-mediated trapping of the covalent enzyme-DNA complex.
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PMID:Two independent amsacrine-resistant human myeloid leukemia cell lines share an identical point mutation in the 170 kDa form of human topoisomerase II. 131 90

Treatment of human K-562-J leukemia cells for 1 h with the topoisomerase II-reactive drugs VP-16, VM-26, or mAMSA resulted in a dose-dependent inhibition of proliferation and in an increase in the percentage of cells staining positive for hemoglobin, a marker of erythroid differentiation. Staining for hemoglobin of up to about 60% of the cells was observed at 20 microM VP-16, 1 microM VM-26, and 8 microM mAMSA. Such treatment also caused a G2/M arrest in the cell cycle. Incubation of the cells with radiolabeled VP-16 indicated that the induced erythroid differentiation was not due to continuous cell exposure to a residual amount of the drug. VP-16-induced erythroid differentiation was also not affected by DNA, RNA, or protein synthesis inhibitors. Differentiation induction and the G2/M arrest evoked by VP-16, VM-26, and mAMSA were, however, reduced in the presence of novobiocin. Our results indicate that topo-reactive drugs that cause G2/M arrest in the K-562-J cell cycle can induce in these cells erythroid differentiation after a short and irreversible interaction with their target molecule(s).
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PMID:The effect of topoisomerase inhibitors on the expression of differentiation markers and cell cycle progression in human K-562 leukemia cells. 133 Jun 53

We examined the feasibility of maintaining specific plasma concentrations of ara-C and VP-16 in children with AML. Sixty-one children were treated with 6 sequential cycles of intensive chemotherapy consisting of: (1) cytarabine (ara-C)/VP-16, (2) ara-C/daunorubicin (Dauno), (3) VP-16/amsacrine (m-AMSA), (4) VP-16/5-azacytidine (5-Az), (5) ara-C/Dauno, and (6) ara-C/VP-16. Fifty-nine children had de novo AML, and 2 had a previous myelodysplastic syndrome. The number of patients with each specific FAB subtype was: M0-1; M1-7; M2-24; M3-7; M4-5; M5-11; and M7-6. Simultaneous continuous infusions of ara-C and VP-16 (cycle 1) given at individualized doses to achieve drug plasma concentrations of 1 microM and 30 microM, respectively, produced complete remission (CR) in 26 of 61 patients (43%); an additional 17 patients entered CR after Dauno/ara-C (cycle 2), and one patient required 4 cycles of chemotherapy to achieve CR (total CR rate = 72%). The preliminary 2-year event-free survival (EFS) for patients with FAB-M1 and -M2 AML was only 15% versus 40% for those with FAB-M4 and -M5 AML. Overall, 21 of the 61 patients remain in CR (2-yr EFS = 29%). We conclude that intense treatment with ara-C and VP-16 at doses individualized to achieve target plasma concentrations is feasible although severely myelosuppressive. It results in an acceptable CR rate, but does not improve EFS.(ABSTRACT TRUNCATED AT 250 WORDS)
Leukemia 1992
PMID:Current strategies for treatment of acute myeloid leukemia at St Jude Children's Research Hospital. 137 92

The coumermycin antibiotic novobiocin, which interacts with the nuclear enzyme topoisomerase II, produced supra-additive toxicity to WEHI-3B D+ leukemia cells at clinically achievable concentrations, when combined with teniposide (VM-26) or etoposide (VP-16). Simultaneous exposure of cells to both agents was required for maximum efficacy of the combination. Novobiocin also produced supra-additive toxicity to A549 human lung carcinoma cells when combined with VM-26 or VP-16. At concentrations above the peak plasma levels achievable in patients, novobiocin lost its potentiating activity. Exposure of WEHI-3B D+ cells to novobiocin did not modify the cytotoxicity produced by the topoisomerase II inhibitor m-AMSA, whereas, in contrast, novobiocin antagonized the cytotoxicity of m-AMSA in A549 cells. Although it has been suggested that inhibitors of the syntheses of DNA and RNA interfere with the cytotoxic activity of the epipodophyllotoxins, maximum potentiation of the cytotoxicities of VP-16 and VM-26 occurred at novobiocin concentrations that decreased the rates of synthesis of both DNA and RNA in WEHI-3B D+ cells by about 50%. The number of DNA-topoisomerase-II covalent complexes stabilized by VM-26 in WEHI-3B D+ cells was greatly increased when cells were exposed simultaneously to VM-26 and novobiocin for 1 hr, but not when cells were treated with m-AMSA and novobiocin for the same period of time. Novobiocin did not affect the amount of covalent complexes produced by VM-26 in isolated nuclei, suggesting that the potentiating activity of novobiocin was not due to its direct interaction with the nuclear topoisomerase II enzyme. Our findings suggest that therapeutic levels of novobiocin may be capable of enhancing the clinical activities of VP-16 and VM-26.
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PMID:Potentiation by novobiocin of the cytotoxic activity of etoposide (VP-16) and teniposide (VM-26). 137 86

Pretherapy bone marrow (BM) aspirates of 143 patients with acute myeloid leukemia (AML) were incubated simultaneously with bromodeoxyuridine (BrdU) and tritiated cytosine arabinoside ([3H]Ara-C) to determine the labeling index (LI) and extent of [3H]Ara-C incorporation. Of 143 AML patients, 121 received high-dose Ara-C (HDAra-C) as a single agent for induction therapy (55 newly diagnosed, 66 in first relapse), whereas 22 received HDAra-C plus mAMSA. The data demonstrate that a subset of patients who will fail HDAra-C remission induction therapy because of drug-resistant disease can be prospectively identified on the basis of the low amount of Ara-C incorporated by their leukemia cells.
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PMID:Relationship of [3H]Ara-C incorporation and response to therapy with high-dose Ara-C in AML patients: a Leukemia Intergroup study. 142 99

We examined the effects of CI-973 (supplied by Parke-Davis) on several human leukemia cell lines and a Chinese hamster ovary (CHO) line and their drug-resistant counterparts. The cell lines used were HL-60, HL-60/mAMSA, HL-60/DOX, KBM3, KBM3/mAMSA 6, KBM3/mAMSA 6(85), CHO, and CHO/AC-7. DOX, mAMSA, and AC-7 indicate resistance to doxorubicin, amsacrine, or 1-beta-D-arabinofuranosylcytosine, respectively. Cells were incubated with CI-973, and the effect was evaluated by two methods: growth inhibition assay and inhibition of colony formation. All cell lines examined were inhibited by CI-973; two of three amsacrine-resistant lines and the one cytarabine-resistant line demonstrated collateral sensitivity. At equivalent dosages, a 4-day exposure provided much greater cell kill than a 1-h exposure. Clonogenic assay showed exponential killing over 3 log units. Maximum CI-973 levels required to kill 50% of cells were 10-fold lower than the peak plasma levels achieved in a phase I solid tumor study. A continuous infusion phase I study in acute leukemia has been initiated.
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PMID:CI-973, a new platinum derivative with potential antileukemic activity. 163 26

Phorbol-12-myristate 13-acetate (PMA), a stimulator of protein kinase C, dramatically decreased topoisomerase II-reactive drug-induced DNA cleavage in HL-60 human leukemia cells. The effect of staurosporine, an inhibitor of protein kinase C, on drug-induced, topoisomerase II-mediated DNA cleavage was quantified in the same cells. Staurosporine decreased the magnitude of 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA)- and etoposide-induced DNA cleavage in a dose- and time-dependent fashion. Measurement of several parameters of cell proliferation revealed no clear and uniform correlation between staurosporine's inhibition of these parameters and its effects on drug-induced DNA cleavage. A direct comparison with PMA's effects on drug-induced DNA cleavage showed that whereas PMA's inhibition of etoposide-induced cleavage was much greater than its inhibition of m-AMSA-induced cleavage, the magnitude of staurosporine's effect on the cleavage produced by the two topoisomerase II-reactive drugs was similar. Thus, although PMA stimulates protein kinase C and staurosporine inhibits this enzyme, it is unlikely that the actions of either on topoisomerase II-reactive, drug-induced DNA cleavage are mediated directly via protein kinase C. Furthermore, it is likely that the mechanisms by which PMA and staurosporine inhibit topoisomerase II-reactive drug-induced cleavage are different.
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PMID:The effect of staurosporine on drug-induced, topoisomerase II-mediated DNA cleavage in human leukemia cells. 166 Mar 53

Amsacrine (AMSA) and cyclocytidine were studied as retrieval therapy in 122 pediatric patients with acute nonlymphoblastic leukemia (ANLL). Patients either failed to achieve sustained initial remissions or were in relapse. Induction therapy consisted of intravenous (IV) AMSA (75 mg/m2) from days 1 to 5 and subcutaneous cyclocytidine (600 mg/m2) from days 1 to 7. Maintenance therapy consisted of IV etoposide (VP-16) (100 mg/m2) for 5 days and IV AMSA (100 mg/m2) on day 1. Of 122 patients, 109 were evaluable. There were 13 early deaths. Ninety-six patients received adequate therapy defined as completion of two courses of therapy. Of these 96 patients, 52 achieved complete remission. Fifteen of 33 patients who failed initial induction achieved complete remission. Eighteen of 39 patients who were resistant to anthracyclines had complete responses. There was no direct evidence of AMSA-induced cardiotoxicity. Remission duration was 28 days to 3 or more years (median, 98 days). AMSA and cyclocytidine were effective retrieval therapy for patients who were in relapse or unresponsive to frontline therapy. Duration of remission was short (median, 98 days).
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PMID:Successful reinduction therapy with amsacrine and cyclocytidine in acute nonlymphoblastic leukemia in children. A report from the Childrens Cancer Study Group. 170 36

In the present study we demonstrate that Aza-dC in combination with Amsacrine has major antileukaemic properties in patients who have not already received extensive Ara-C therapy. Eight out of 11 patients in their first relapse of acute leukaemia achieved complete remission. Cross resistance between Ara-C and Aza-dC was revealed by the lack of antileukaemic activity in five patients with with Ara-C resistant leukaemia. Combination therapy with Aza-dC/Ams-acrine induced a considerable period of a granulocytopenia (28-35 days), while the toxic effect on erythro- and megakaryopoiesis was comparable to that reported for high dose Ara-C/Amsacrine chemotherapy. Remarkable is the long disappearance time for leukaemic blast cells in bone marrow, i.e. 3-5 weeks in some cases. Analysis of cell membrane markers showed a loss of the early differentiation antigens CD34 and CD33 from leukaemic bone marrow cells after 7 days of Aza-dC treatment, which is suggestive of leukaemic cell differentiation. In the small group of patients tested for DNA hypomethylation no association existed between the degree of hypomethylation and clinical response. Non-haematologic side effects were considerable in patients receiving the highest dosages of Aza-dC and consisted of severe, although usually reversible, gastrointestinal and neurological complications. In comparison with Ara-C, Aza-dC causes less nausea and vomiting and is therefore better tolerated.
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PMID:The antileukaemic activity of 5-Aza-2 deoxycytidine (Aza-dC) in patients with relapsed and resistant leukaemia. 171 50

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


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