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)

Treatment of Friend leukemia cells for 18 hours with 9,10-anthracenedione, 1,4-bis[[(2-hydroxyethyl)amino]ethyl]amino]-, diacetate (ANT) at concentrations up to 1.0 microgram/ml induced significant changes in cell metabolism and structure. Alterations in cell nucleic acid content were detected in cells stained with acridine orange under conditions such that DNA and RNA contents could be measured simultaneously by flow cytometry. Cells treated for 18 hours with ANT at concentrations of 0.05-0.1 microgram/ml became partially blocked at the G2 phase. In addition, about 30% of the cells became polyploid and demonstrated diplochromosomes at the 8C level of mitosis. The nuclear chromatin of blocked cells had an altered structure as reflected by a change in sensitivity of DNA in situ to denaturation induced by low pH. All viable cells treated with ANT for 18 hours at concentrations of 0.4-1.0 microgram/ml were blocked in G2 phase. These cells had significantly more RNA than did untreated cells. Transmission electron microscopic observations of thin-sectioned cells suggested that this increased RNA content in ANT-treated cells was mostly due to an approximately 50% increased cell diameter and partly due to a disproportionate increase in nucleolar size. In addition, electron microscopy revealed that ANT caused increased chromatin condensation and granulation. The drug had no apparent effect on production of the endogenous Friend murine leukemia virus.
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PMID:Effects of 9,10-anthracenedione, 1,4-bis[[2-[(2-hydroxyethyl)amino]-ethyl]amino]-, diacetate on cell morphology and nucleic acids of friend leukemia cells. 692 97

In patients with chronic myelogenous leukaemia (CML), we have found the break points on the long arm of chromosome 22 (22q) are variable (heteromorphic or polymorphic). Consequently, the Philadelphia (Ph1) chromosome is heteromorphic in size for the long arm. Based upon the break points and the relative size of chromosome 22, four types of Ph1 chromosomes are proposed. They are: Types I (very large), II (large), III (average) and IV (small) with the break points at bands 22q13.3, 22q13.1, 22q12 and 22q11.3, respectively. The break points are arbitrary and should not be considered absolute since they are based on length differences. In two cases the Ph1 chromosome involved a translocation between chromosome 9 and 22, and the other two cases chromosome 1 or 12. Because Types I and II are hard to recognize by conventional techniques, the RFA technique (R. band by fluorescence with acridine orange) must be performed on all cases. An earlier contention that only chromosome 22 band 12 is concerned with abnormal myeloid cell proliferation in human leukaemia is rejected. Furthermore, break points are not restricted at the junction of 22ql and q2 and 22q2 and q3 and can happen anywhere on the long arm of chromosome 22.
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PMID:Heteromorphisms of the Philadelphia (Ph1) chromosome in patients with chronic melogenous leukaemia (CML). I. Classification and clinical significance. 693 5

Flow cytometry of cellular DNA content revealed ploidy abnormalities in 15% of 170 patients with various leukemias, in 50% of 26 patients with malignant lymphomas, and in 68% of 110 patients with multiple myeloma, for an overall incidence of DNA content abnormality of 37% in 306 patients with hematologic malignancies. Since the incidence of ploidy abnormality in over 100 solid tumors exceeded 90%. DNA flow cytometry is also ideally suited to screen for bone marrow metastases. Cell separation by centrifugal elutriation was shown to permit enrichment of aneuploid cells, including one example where cells with abnormal DNA content were not recognized in the unfractionated sample. Biparametric measurements of acridine orange-stained cells for DNA and RNA content analysis were suitable to enhance the discriminatory power of flow cytometric detection of lymphoma and myeloma tumor cells in heterogeneous cell populations of bone marrow and lymph nodes. DNA/RNA measurements in leukemia, (the disease category with the lowest incidence of abnormal DNA mode) revealed a markedly higher mean RNA content in acute myeloid leukemia compared with normal or acute lymphoblastic leukemia bone marrow. While these different RNA content patterns were found in whole marrow, cell separation by centrifugal elutriation of normal marrow disclosed cell subpopulations of myeloid precursor cells with a RNA content pattern similar to that of unseparated AML marrow. Hence, the described differences in RNA content between normal and AML marrow seem to be related to the greater heterogeneity of differentiated cells in normal marrow and per se do not appear to be a unique feature of the leukemia disease process.
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PMID:Characterization of hematologic malignancies by flow cytometry. 700 71

The mutagenicity of DNA-binding affinity of members of a series of acridine-substituted derivatives of 4'-(9-acridinylamino)methanesulphonanilide (AMSA) have been compared. The series includes compounds ranging from highly active to inactive in the L1210 murine leukaemia. Binding to DNA was measured by an ethidium displacement technique, with a correction being made for acridine-induced quenching of ethidium. Mutagenicity was assessed by measuring the reversion frequencies of the frameshift tester strain Salmonella typhimurium TA1537 in liquid culture. The results indicate that maximum mutagenicity is found in a "window" of DNA-binding affinities between 10(6) and 5 X 10(6) M-1 (determined at 0.01 ionic strength). Compounds with binding affinities below 10(6) M-1 generally lacked both antitumour and mutagenic activity, whereas those with affinities above 5 X 10(6) M-1 were active against L1210 leukaemia but virtually inactive in inducing frameshift mutations.
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PMID:The relationship between frameshift mutagenicity and DNA-binding affinity in a series of acridine-substituted derivatives of the experimental antitumour drug 4'-(9-acridinylamino)methanesulphonanilide (AMSA). 702 71

A series of 9-anilinoacridine derivatives has been compared in terms of DNA binding, ability to inhibit the growth of L1210 murine leukaemia cells in vitro, and ability to induce the formation of respiration-deficient (petite) mutations in Saccharomyces cerevisiae. The acridine ring in the derivatives was either unsubstituted, or substituted with amino groups at the 3 and/or 6 positions. The 9-anilino group was para-substituted with a variety of substituents. 3-Aminoacridine, 3,6-diaminoacridine (proflavine) and ethidium were included for comparison. The results show that: (i) at least one acridinyl amino group is necessary for conferring petite inducing activity in the yeast system; (ii) for 3-amino-9-anilinoacridine congeners, small anilino substituents provide compounds which resemble proflavine in their ability to produce petite mutants, whereas large substituents abolish activity; (iii) the 3,6-diamino-substituted anilinoacridines resemble ethidium rather than proflavine in being highly efficient inducers of petites; (iv) the requirements for optimal activity in L1210 leukaemia cell cultures are different to those for petite formation in yeast. It is concluded that the size of the anilino substituent, as well as its contribution to DNA binding, is critical in conferring biological activity in each system.
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PMID:Induction of petite formation in Saccharomyces cerevisiae by experimental antitumour agents. Structure--activity relationships for 9-anilinoacridines. 703 62

The studies described here explored the staining of acute leukemia cells with acridine orange (AO). The red fluorescence curve of AML specimens was usually bimodal, suggesting the presence of subpopulations of cells which have different RNA contents. In almost every AML specimen, small leukemic blast cells comprised at least part of the "low RNA content" subpopulation. Residual granulocytes and lymphocytes also contributed to this population. Frequently, the green fluorescence, indicative of the binding of AO to DNA, was slightly less in these cells than in the majority of cells present. There was no evidence however, that the leukemia cells with these characteristics represented a G0 or kinetically quiescent population of cells. In ALL specimens, the presence of multiple cytogenetically distinct clones was easily detectable in AO stained specimens. The red fluorescence curve of G0/G1 ALL cells was unimodal.
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PMID:The study of acute leukemia cells by means of acridine orange staining and flow cytometry. 751 46

A series of pyrimidoacridine derivatives with two basic side chains, 7a-e, was synthesized, as potential antitumor drugs, starting from 2-[2-(dimethylamino)ethyl]-6-chloropyrimido[5,6,1-de]acridine-1,3, 7- trione (6) and a suitable (alkylamino)alkylamine. The products 6 and 7a-e showed significant cytotoxic activity in vitro against L1210 leukemia. Compounds 7a,d were 2 orders of magnitude more cytotoxic than ametantrone. All compounds were also examined for their activity on LoVo and resistant LoVo/Dx cell lines. Unlike ametantrone, the compounds have shown to be able to overcome the multidrug resistance. Compounds 7a,d, the two most active in vitro, were tested in vivo against murine P388 leukemia showing good activity.
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PMID:Synthesis of (dialkylamino)alkyl-disubstituted pyrimido[5,6,1- de]acridines, a novel group of anticancer agents active on a multidrug resistant cell line. 765 Jun 82

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

We report the synthesis, DNA-binding properties and antitumor activity of ThiaNetGA, a hybrid molecule in which are conjugated a thiazole-lexitropsin and an intercalating anilinoacridine chromophore. This combilexin molecule binds to DNA via a bimodal process involving minor groove binding of the lexitropsin moiety and intercalation of the acridine moiety. The uptake and distribution of the hybrid in L1210 leukemia cells were investigated by ESR spectroscopy using a spin-labeled derivative. The nitroxide-containing conjugate accumulates preferentially in the cell nuclei and rapidly saturates the nuclear receptor sites. Both in vitro and in vivo assays indicate that the drug is practically nontoxic but exhibits moderate antitumor activity against P388 leukemia cells in mice.
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PMID:Antitumor combilexin. A thiazole-containing analogue of netropsin linked to an acridine chromophore. 784 80

The effect of exogenous homocysteine thiolactone (Hcy) on apoptosis initiated by 3-deazaadenosine (c3Ado) was studied in human leukemia HL-60 cells. Flow cytometric analysis allowed evaluation of the relative number of apoptotic cells (APC) to apoptotic bodies (APB) with a sub G0/G1 DNA content. Addition of 1 mM Hcy to HL-60 cells exposed to 5 to 100 microM c3Ado was followed by a large increase in the number of APC and a simultaneous decrease in the number of APB. The effects of Hcy on both the formation of APC and APB was dose-dependent; however, Hcy concentrations above 250 microM were required for inhibition of APB formation to take place. Fluorescence microscopic examination of unfixed cells stained with acridine orange demonstrated different morphology of APC between cultures treated with c3Ado or c3Ado plus Hcy. Whereas APC in cultures treated with 100 microM c3Ado displayed pronounced cytoplasmic membrane blebbing, only minor blebbing was displayed by APC in cultures treated with 25 microM c3Ado and 1 mM Hcy. Extensive nuclear fragmentation was observed in APC regardless of Hcy addition. By cell sorting we demonstrate the presence of APC with the same DNA content as viable G0/G1 and S-phase cells in cultures treated with 25 microM c3Ado and 1 mM Hcy, indicating that cells in all cell cycle phases undergo apoptosis in these cultures. Neither the formation of APC nor APB in apoptosis initiated by cycloheximide or dactinomycin were influenced by 1 mM Hcy. The Hcy effects on c3Ado apoptosis were abrogated in part by 3-deaza-(+/-)-aristeromycin, a more specific and potent inhibitor of S-adenosylhomocysteine hydrolase.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Homocysteine increases the relative number of apoptotic cells and reduces the relative number of apoptotic bodies in HL-60 cells treated with 3-deazaadenosine. 801 68


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