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)

N-[2-(Dimethylamino)ethyl]acridine-4-carboxamide (AC; NSC 601316) is a chemically novel antitumour agent which is thought to interact with DNA topoisomerase II and which has DNA binding properties which are distinct from other acridine derivatives such as amsacrine and its disubstituted analogue CI-921. AC is one of the most active agents, experimental or clinical, against the Lewis lung carcinoma in mice. AC is the first acridine derivative in our hands to show higher activity against cultured Lewis lung cells than against leukaemia lines. AC is more active against two human leukaemia cell lines (U-937 and Jurkat) than against a melanoma line (MM-96) and is inactive against the HT-29 human colon line. With all cell lines tested, cytotoxicity was higher at AC concentrations of 3-6 microM than at 15-20 microM. AC at a concentration of 20 microM inhibited the cytotoxicity of amsacrine and CI-921, but not that of another topoisomerase-directed drug doxorubicin. A Lewis lung line which had been cultured for a long period was less sensitive than a line freshly isolated from mice, but sensitivity of the cultured line recovered after it was multiply passaged in vivo. Long-term cultures may therefore be less appropriate than short-term cultures for predicting effectiveness of AC in vivo.
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PMID:Selectivity of N-[2-(dimethylamino)ethyl]acridine-4-carboxamide towards Lewis lung carcinoma and human tumour cell lines in vitro. 270 82

Fluorescence flow cytometry was used to generate DNA histograms of acridine orange stained leukemic cell populations in G0-G1 phase of the cell cycle. Complexes of the intercalating agent, acridine orange, with double-stranded DNA in situ, emit green fluorescence upon excitation with blue laser light. The histograms were evaluated by first determining the standard deviation of the fluorescence intensity relative to the mean channel of fluorescence, i.e., the coefficient of variation, and then dividing the coefficient of variation of a patient's sample by that of a control sample (rCV). The mean rCV of cell populations of acute lymphoblastic leukemia (31 patients) differed significantly from that of nonlymphoblastic leukemia (21 patients). When cells were treated with a solution of citric acid and magnesium sulfate prior to their staining with acridine orange, the mean rCV of cell populations of acute lymphoblastic leukemia increased while that of acute nonlymphoblastic leukemia decreased compared to their respective pretreatment values. The mean difference of rCVs between untreated and treated cells (rCVD) within each disease category was statistically significant. A logistic regression model, based on rCVD, confirmed the conventional classification of acute lymphoblastic leukemia and acute nonlymphoblastic leukemia cells in 90% of the cases.
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PMID:Binding of acridine orange to DNA in situ of cells from patients with acute leukemia. 273 Nov 83

In an investigation of a new class of deoxyribonucleic acid (DNA)-intercalating antitumor agents, novel acridinyl-substituted uracils have been synthesized and evaluated for activity against L1210 leukemia in vivo, and against bacteria and fungus. These compounds were prepared by the novel enamine reaction between 9-chloroacridines and 6-aminouracils. The positional effects of substituents on the acridine ring showed that compounds bearing electron-withdrawing groups at the 3- or 6-position of the acridine ring were the most active.
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PMID:Acridine derivatives. III. Preparation and antitumor activity of the novel acridinyl-substituted uracils. 275 80

Suppression of the green fluorescence of acridine orange by 5-bromodeoxyuridine incorporation into cellular DNA was measured by flow cytometry. Bone marrow cells from normal volunteers and patients with chronic myelogenous leukemia acute lymphocytic leukemia acute myelogenous leukemia and multiple myeloma were incubated with BUdR in vitro. By 24 h acridine orange stained cycling cells that had synthesized DNA in the presence of BUdR were differentiated from quiescent cells as a second peak with quenched green fluorescence (DNA). After 72 h in culture 11-65% of the G0/G1 cells from normal bone marrows and bone marrows with myeloid leukemia were identified as cycling in culture by the presence of a second peak with quenched green fluorescence. A greater percentage of cells with BUdR quenched AO fluorescence was associated of acridine orange was higher in the cycling cells that had synthesized DNA in the presence of BUdR than in the non-cycling G0/G1 cells. In one patient with AML there was quenching of the DNA fluorescence of the aneuploid population but not the diploid population indicating that the aneuploid leukemia cells were proliferating. In contrast in patients with multiple myeloma, the quenched fluorescence of the diploid cell population and not the aneuploid cells, indicated that the diploid cells were proliferating. The cells from patients with untreated ALL failed to proliferation prohibiting an in vivo assessment of growth. Although measurements of proliferation obtained by this method are clearly influenced by the cell's adaptation to culture, measurement of BUdR quenching of acridine orange fluorescence is technically feasible and can identify and allow characterization of the cycling population of cells.
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PMID:5-bromodeoxyuridine (BUdR) quenching of acridine orange fluorescence distinguishes cycling and non-cycling normal and malignant bone marrow cells in vitro. 279 84

4'-(9-Acridinylamino)methanesulfon-m-anisidide (m-AMSA) is a DNA intercalating 9-aminoacridine with clinical activity in adult acute leukemia. m-AMSA has been shown to produce protein-linked DNA strand breaks in mammalian cells through an interaction with the nuclear enzyme DNA topoisomerase II. We have compared the effects of m-AMSA and several acridine analogues (9-aminoacridine; A, NSC 343499; B, SN 16507; C, NSC 140701; D, SN 13553) on DNA integrity and cell survival in L1210 leukemia in vitro. Cells (or isolated nuclei) were treated with drugs (0.1-50 microM) for 0.5-1.0 h and subsequently analyzed using the alkaline elution technique. All drugs, except Compound D, produced DNA-protein cross-links (DPC) in L1210 cells. At 1 microM, potency was in the order, C greater than m-AMSA greater than B greater than A much greater than 9-aminoacridine. In isolated nuclei, DPC and single-strand breaks were produced in essentially a 1:1 ratio, which is consistent with topoisomerase II-mediated protein-linked DNA breaks. Potency differences were less pronounced in nuclei than in cells. In isolated nuclei, Compound D produced extensive DPC not associated with single-strand breaks, which suggests a more complex activity for this compound. Colony formation assays demonstrated the cytotoxicity of most of these acridine analogues (C greater than B greater than A approximately equal to m-AMSA much greater than D = 9-aminoacridine). Correlation of DPC with cell kill gave similar curves for each compound. These results are evidence for a causal relationship between drug-induced topoisomerase II-mediated DNA breaks and cytotoxicity.
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PMID:Topoisomerase II-mediated DNA damage produced by 4'-(9-acridinylamino)methanesulfon-m-anisidide and related acridines in L1210 cells and isolated nuclei: relation to cytotoxicity. 282 87

DNA, RNA, and/or protein cellular content were studied by flow cytometry in 52 cases of acute myeloid leukemia before and on day 4 of remission induction treatment. Bone marrow (BM) samples were stained after fixation by acridine orange for DNA and RNA content (37 cases) and by propidium iodide and fluorescein isothiocyanate for DNA and protein content (52 cases). A positive correlation was found between pretreatment protein content and BM blast involvement: the higher the percentage of blasts in BM smears the higher the mean protein content (p less than 0.05). Protein content was higher in monoblastic leukemia (M4 and M5) than in the granulocytic types (M1, M2, M3) (p less than 0.05). S + G2 + M was higher in patients with protein content below 80 arbitrary units than in the subgroup with protein content above this threshold (p less than 0.05). Pretreatment RNA content, estimated by the RNase-sensitive fraction of G1 cells, was significantly higher in undifferentiated and M1 leukemias than in the other cytological groups (p less than 0.0001). This fraction was higher in patients who subsequently achieved complete remission, but it was not related to BM blast involvement or proliferative fraction of cells. During cytostatic treatment the changes in RNA and protein content did not follow a typical pattern. The connections between variations of DNA, RNA, and protein content and prognosis are examined and their possible relation to drug-induced blast cell maturation is discussed.
Leukemia 1988 Aug
PMID:DNA, RNA, and protein content in adult acute myeloid leukemia: effects of cytostatic drugs in vivo. 316 79

Antitumor activity against the Lewis lung carcinoma in mice is reported for the series of 36 acridine-substituted derivatives of the antileukemia agent amsacrine. This series is the one from which the analogue N,5-dimethyl-9-[(2-methoxysulfonylamino)phenylamino]-4-acridinecarboxamide (CI-921), presently in clinical trial, was chosen. The analogues also were tested in vitro by comparing growth inhibition data [IC50 values (concentration required to reduce growth of cultured cells to 50% of that of untreated cultures)], using L1210 murine leukemia cells and HCT-8 human colon carcinoma cells. Determined IC50 values were highly dependent on the culture medium used, and it was found that the presence of ascorbate in the medium had a major effect on the stability of compounds to oxidation. A survey of 115 analogues of amsacrine indicates that a low ratio of IC50 values (HCT-8/L1210) is necessary but not sufficient for good antitumor activity against the solid tumor. DNA binding constants did not in themselves predict activity, although they were related to dose potency. Other factors, such as drug lipophilicity, acridine base strength, and drug solubility, also are involved, probably in providing effective drug distribution. It is concluded that in vitro assay data provide information useful for drug design but that other factors also are important for in vivo activity.
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PMID:Derivatives of amsacrine: determinants required for high activity against Lewis lung carcinoma. 334 11

A series of derivatives of 9-anilinoacridine related to the anti-leukaemia agent amsacrine have been tested in continuous exposure growth inhibition assays to determine the degree of cross-resistance in the Adriamycin-resistant P/ADR murine leukaemia line. Measured IC50 values for the two cell lines were only poorly correlated (r = 0.51), and cross-resistance as measured by the ratio of IC50 values varied from 2-fold and 272-fold. A high degree of resistance was found to be associated with the presence of amino or substituted amino groups on the acridine ring system. Logarithmic IC50 values were determined for other cell lines (L1210 leukaemia, Lewis lung carcinoma and HCT-8 human colon carcinoma) and were compared with those for the P388 lines to determine the degree of linear correlation. HCT-8 values were strongly correlated with P/ADR values (r = 0.84) while L1210 values correlated strongly with those of the sensitive P388 line (r = 0.98). Values for Lewis lung cells showed an intermediate pattern and correlated with a linear combination of values for both P388 lines (r = 0.88). Examination of available IC50 values for a number of rodent and human cell lines indicates that their sensitivity patterns are either P388-like or else intermediate between P388 and P/ADR. The series of amsacrine derivatives may be useful in characterizing the nature and degree of multidrug-resistance in cultured cell lines.
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PMID:Relationship between the structure of analogues of amsacrine and their degree of cross-resistance to adriamycin-resistant P388 leukaemia cells. 335 8

Mouse leukaemia L1210 cells were subjected to hyperthermia (43.0 +/- 0.05 degrees C, water bath) and photodynamic therapy (50 micrograms/ml haematoporphyrin derivative (HpD), 630 +/- 5 nm at 0.1 mW/cm2) for varying lengths of treatment time in different sequences. Dose-response curves showed that the two modalities interact to make the combination more cytotoxic than the sum of the separate individual treatments, and that a determining factor is the intracellular concentration of HpD of tumour cells during hyperthermia. High cytotoxic (synergistic) effects of photodynamic therapy (PDT) were obtained when PDT was performed after hyperthermia following HpD administration. However, only additive cytotoxic effects were found, when hyperthermia was performed after HpD administration and PDT. These cytotoxic data were supported by DNA damage (the increase in single-stranded DNA) as revealed by flow cytometry in cells stained with acridine orange (AO). These in vitro experiments suggest that clinical applications of PDT after hyperthermia with HpD injection might be useful.
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PMID:The effect of hyperthermia on murine leukaemia cells in combination with photodynamic therapy. 336 Nov 67

A series of phenanthroline analogues of the 9-anilinoacridine anti-leukaemic drug amsacrine were prepared and evaluated, with the aim of providing more weakly-basic derivatives which retained high levels of DNA binding. All the phenanthroline derivatives were stronger DNA-binding ligands than the corresponding acridine compounds, and the 1,7- and 1,8-phenanthrolines were weaker bases by 2 pKa units. The 1,10-phenanthroline derivative showed superior in vivo activity against the P388 leukaemia and the Lewis lung solid tumour than the corresponding acridine derivative amsacrine, but the other phenanthroline compounds did not have improved activity.
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PMID:Amsacrine analogues with extended chromophores: DNA binding and anti-tumour activity. 344 85


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