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)

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 role of amsacrine in inducing remission in patients with cardiac disease and acute leukemia was evaluated. There were 17 patients with acute myelogenous leukemia (AML), six with acute lymphocytic leukemia (ALL), and one with biphenotypic leukemia. In this series of 24 patients whose disease had relapsed and who had reduced left ventricular ejection fraction, nine had a complete remission, seven with AML and two with ALL. In addition, four of six with newly diagnosed acute leukemia and reduced left ventricular ejection fraction also responded. Among nine patients who underwent endomyocardial biopsy, none had morphologic changes of sufficient degree to account for drug-induced heart failure. Patients with preexisting arrhythmias received amsacrine without incident if their serum potassium level was higher than 4.0 mEq/l at the time of drug administration. Amsacrine is safe and effective therapy for patients with acute leukemia and cardiac disease.
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PMID:Amsacrine is safe and effective therapy for patients with myocardial dysfunction and acute leukemia. 187 70

The New Zealand Acute Myeloid Leukaemia (AML-1) study ran from 1985 to 1988. Ninety-two patients with acute myeloid leukaemia between the ages of 13-65 were entered. Remission induction treatment consisted of cytosine arabinoside (Ara-C) 100 mg/m2 12 hourly for seven days and daunorubicin (DNR) 45 mg/m2 daily for three days. Fifty-six patients entered remission (61%). The patients were randomised at diagnosis to receive either three further courses of Ara-C (five days) and DNR (two days) in the same dosage or three courses of VP16 100 mg/m2 daily for five days and one dose of mAMSA of 200 mg/m2 as postremission consolidation. No difference in survival between these two consolidation treatments was seen (p = 0.96). The overall survival of the original 92 patients is 13% with a minimum follow up of two and a half years. However, for those patients solely treated with the trial protocol, disease free survival at 2% is poor. The poor long term results could reflect the relatively low intensity consolidation treatment used in this study. However, since a majority of patients presenting in New Zealand with acute myeloid leukaemia between these ages were entered into the trial, the results could also reflect the relative lack of selection bias which affects many published studies of acute leukaemia treatment.
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PMID:Acute myeloid leukaemia: results of the New Zealand AML-1 study. The Leukaemia Study Group of the New Zealand Society for Haematology. 192 3

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

Several new cytostatic drugs have entered clinical phase I-II studies for the treatment of leukemia: the most promising are pyrimidine analogs such as 5-aza-cytidine, 5-aza-2'-deoxycytidine, 5-aza-cytosine arabinoside, and 2',2'-difluorodeoxycytidine. Fludarabine, a fluorinated purine analog, appears to be active in CLL and multiple myeloma. Deoxycoformycin, an adenosine analog, showed good activity in the treatment of hairy cell leukemia and T-cell neoplasias. 2-chloro-deoxyadenosine has recently been introduced into the treatment of CLL and hairy-cell leukemia refractory to deoxycoformicin. Tiazofurin, an antimetabolite which interferes with nicotine-adenine-dinucleotide (NAD) metabolism, has been applied in CML blast crisis. Other agents include 13-cis retinoic acid and 1, 25-dihydroxy vitamin D3 as differentiation inducers, and homoharringtonine, an alkylating agent which is widely used for ANLL treatment in China. Among new anthracyclines, aclarubicin, idarubicin, THP-adriamycin and fluoro-adriamycin should be mentioned. Mitoxantrone, a substituted anthraquinone, has successfully been applied in the treatment of relapsed and refractory ANLL. Amsacrine (m-AMSA), finally, is a synthetic aminoacridine which intercalates into DNA and inhibits DNA topoisomerase II. m-AMSA is not cross-resistant to anthracyclines and has been particularly active in ANLL treatment. Studies using m-AMSA alone or in combination revealed comparable results to anthracycline--containing regimens. Cardiotoxicity of the anthracycline congestive type has not been observed with m-AMSA. The EORTC Leukemia Cooperative Group has successfully used m-AMSA in several trials prepositioning this drug stepwise: from relapsed and refractory ANLL, into intensive maintenance treatment during first remission in ANLL, and, still on-going, into intensive consolidation.
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PMID:New drugs in the treatment of acute and chronic leukemia with some emphasis on m-AMSA. 206 23

CEM leukemia cells selected for resistance to VM-26 (CEM/VM-1) are cross-resistant to various other DNA topoisomerase II inhibitors but not to Vinca alkaloids. Since DNA topoisomerase II is a major protein of the nuclear matrix, we asked if alterations in nuclear matrix topoisomerase II might be important in this form of multidrug resistance. Pretreatment of drug-sensitive CEM cells for 2 h with either 5 microM VM-26 or 3 microM m-AMSA reduced the specific activity of newly replicated DNA on the nuclear matrix by 75 and 50%, respectively, relative to that of the bulk DNA. However, neither VM-26 nor m-AMSA affected the relative specific activity of nascent DNA isolated from the nuclear matrices of drug-resistant CEM/VM-1 cells. The decatenating and unknotting activities of DNA topoisomerase II were 6- and 7-fold lower, respectively, in the nuclear matrix preparations from the CEM/VM-1 cells compared to parental CEM cells. Western blot analysis revealed that the amount of immunoreactive topoisomerase II in the nuclear matrices of the CEM/VM-1 cells was decreased 3.2-fold relative to that in CEM cells, but there was no significant difference in the amount of enzyme present in the nonmatrix (1.5 M salt soluble) fractions of nuclei from these cell lines. Increasing the NaCl concentration used in the matrix isolation procedure from 0.2 to 1.8 M resulted in a progressive decrease in the specific activity of topoisomerase II in matrices of CEM/VM-1 but not CEM cells, which suggested that the association of the enzyme with the matrix is altered in the resistant cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Decreased nuclear matrix DNA topoisomerase II in human leukemia cells resistant to VM-26 and m-AMSA. 216 74

We present a case of acute megakaryoblastic leukemia identified by electron microscopy and platelet-specific antibodies. The histological examination of bone marrow showed distinct myelofibrosis. In accordance with recent communications, low-dose cytosine arabinoside treatment (20 mg twice daily s.c. over 21 days) was initiated. The subsequent bone marrow examination showed a severe hypoplasia with persistent blasts. Amsacrine and VP-16 were given without success. Finally the patient died of septicemia without proof of pathogen uninfluenced by antibiotic and antiseptic therapy 6 weeks after diagnosis. Our case report confirms the poor prognosis of acute megakaryoblastic leukemia.
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PMID:Acute megakaryoblastic leukemia: a case report. 218 29

Amsacrine is a DNA intercalating agent which is active against a number of tumours in mice and is used for the treatment of leukaemia in humans. In its DNA-bound form, amsacrine efficiently quenches the fluorescence of ethidium. Fluorescence lifetime studies demonstrate two populations of DNA-bound ethidium. The first, whose fluorescence lifetime is constant at approx. 3 ns and whose proportion increases with increasing amsacrine binding ratio, may comprise molecules bound in close proximity to amsacrine. The second, whose fluorescence lifetime is longer and variable (10-24 ns) and whose proportion decreases with increasing amsacrine binding ratio, may comprise molecules three or more base-pairs away from ethidium. Studies with a number of derivatives of 9-anilinoacridine containing different anilino substituents suggest that the observed wide variation in quenching capacity is correlated with the magnitude of the substituent dipole moment in a particular direction. Consideration of the geometry of the DNA-binding complex indicates that the negative pole of a dipole established in the anilino ring is directed towards a positively charged site on the ethidium molecule. Quenching of ethidium fluorescence may therefore occur where an electron-transfer complex has formed between ethidium and amsacrine molecules. To ascertain whether electron-transfer complex formation is biologically important in the amsacrine series, ethidium quenching has been quantitated and compared with activity against a transplantable neoplasm in mice, the Lewis lung carcinoma. Compounds which strongly quench ethidium fluorescence are in general highly active antitumour agents. The results are discussed in terms of a model where amsacrine has both a DNA-binding and a protein-binding domain, the latter possibly interacting by formation of an electron-transfer complex. The most likely protein-binding domain is on the enzyme topoisomerase II, the target for its cytotoxic activity.
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PMID:The possible role of electron-transfer complexes in the antitumour action of amsacrine analogues. 220 43

Sublines of a human myeloid leukaemia cell line, KBM-3, with increasing degrees of resistance to the antileukaemic agent 4'-(9-acridinlylamino) methanesulphon-m-anisidide (m-AMSA) were evaluated for their response to this drug using a clonogenic assay to measure cell survival and alkaline elution to assess m-AMSA induced DNA strand breakage. Polyacrylamide gel electrophoresis was used to map the protein profiles of the various cell lines. The resistant lines were obtained by intermittent exposure of the KBM-3 cells to the highest tolerated concentration of m-AMSA so that the culture would be repopulated only by the most resistant subpopulation after each exposure. Two distinct phases were apparent during the development of resistance. During the first 14 months of intermittent exposure to maximally tolerated concentrations of m-AMSA, the cells developed low-degree m-AMSA resistance (5-7-fold as compared with the parent line, as measured by cell survival). This low-degree resistance was characterised by a somewhat suppressed level of DNA strand breakage and no measurable change in cellular protein levels. Subsequently, a single escalation of the m-AMSA retreatment concentration resulted in a cell population that was approximately 100-fold resistant, as assessed by cloning. This rapid phenotypic change temporally coincided with the acquisition of an almost complete refractoriness to m-AMSA-induced DNA strand breakage and the loss of a cellular 76 kDa protein. We suggest that the loss of this protein is important for the development of a highly m-AMSA resistant phenotype.
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PMID:Resistance to 4-(9-acridinylamino) methanesulphon-m-anisidide (m-AMSA) in human myeloid leukaemia. 229 90

The cytotoxicity of the anti-leukaemia drug amsacrine (m-AMSA) has been suggested to result from its oxidative metabolism to the corresponding quinonediimine, N1'-methanesulphonyl-N4'-(9-acridinyl)-3'-methoxy-2',5'-cyclohexad iene-1',4'- diimine (mAQDI). The metabolic fate of mAQDI was examined in cultured CHO cells (subline AA8) to identify the end products to be expected following oxidative metabolism of m-AMSA. [Acridinyl-G-3H]-m-AQDI was rapidly accumulated by AA8 cells in phosphate buffered saline with complete conversion in less than one minute to m-AMSA, macromolecular adducts and polar low molecular weight species, each of these three classes being formed in approximately equal amounts. Two of the polar products were chromatographically identical to those formed on reaction of m-AQDI with reduced glutathione. These were identified by 1H NMR spectroscopy as the 1,4-addition product 5'-(S-glutathionyl)-m-AMSA and the previously unreported isomeric 6'-(S-glutathionyl)-m-AMSA. These thiol adducts were also formed rapidly from m-AQDI in deproteinized cell lysates indicating a non-enzymatic process, although the possibility of enzymatic catalysis in intact cells has not been eliminated. The absence of such products in AA8 cells after treatment with m-AMSA places an upper limit of 1% per hour on the rate of its oxidative metabolism in these cells and suggests that generation of m-AQDI is unlikely to be responsible for the cytotoxicity of m-AMSA in cultured tumour cells.
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PMID:The fate of N1'-methanesulphonyl-N4'-(9-acridinyl)-3'-methoxy-2',5'-cyclohexadiene- 1',4'-diimine (m-AQDI), the primary oxidative metabolite of amsacrine, in transformed Chinese hamster fibroblasts. 233 41


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