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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The development of the leukemia-lymphoma complex was studied in AKR/J (H-2k) mice using flow cytometry and staining with acridine orange. Investigation of cytokinetics and of cellular RNA content showed that during the neonatal period all mice had a significant increase of S phase cells in the thymus, bone marrow, lymph nodes and spleen reflecting extramedullary hematopoiesis. Concomitantly, G0/G1 cells were significantly reduced in the thymus, lymph nodes and spleen when compared to 6-week old mice of the same strain. No changes in the cell cycle or in RNA content were observed until 10 months of age in congeneic AKR (H-2b) mice, which do not develop leukemia during the first year of life. In leukemia-prone AKR/J (H-2k) mice, however, it was shown that the first appearance of a leukemic process may be recognized in the thymus by a significant increase of cells in G1 phase of the cell cycle which have a high RNA content. These changes were first seen at 5 months of age before the increased expression of MuLV antigen signals preleukemic alterations at 6 months of age and long before morphological changes appear (8-10 months). Furthermore, at 6 months these mice showed a significant elevation of cells in S phase which always appeared initially in the thymus. By 10 months of age, when the mice were overtly leukemic, these changes had progressed in all lymphoid organs and in the peripheral blood. At the same time a unique population of cells was observed that was characterized by cells in S and G2M with very low RNA content. The method used is applicable to further analysis of the precise locus of development of leukemia in the thymus of AKR/J (H-2k) mice, analysis of the nature of the earliest malignant cells, and investigation of the influence of viruses in the pathogenesis of AKR leukemia.
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PMID:DNA and RNA analysis by flow cytometry of the leukemia in AKR mice. 241 80

Proliferation in total populations of thymocytes from control AKR mice or AKR mice injected intrathymically with MCF 69L1 virus was measured by flow cytometry of acridine orange-stained cells. Cell sorting experiments showed that the majority subpopulations of small cortical and medullary thymocytes in control mice were noncycling and were predominantly in the Go phase of the cell cycle. Of the 15 to 20% cycling thymic lymphoblasts, approximately 50% were in the G1 phase, 35% were in the S phase, and 15% were in the G2 + M phases of the cell cycle. Cycling cells appeared to consist of a major subpopulation with low RNA content and a minority subpopulation with high RNA content. In virus-injected mice, no changes in cell cycling were observed at stage I of leukemogenesis (30 to 40 days postinjection), at which time infection of thymocytes by MCF virus is maximum and constant but no clonality is evident. Thus, MCF virus infection of thymocytes per se does not appear to alter cell proliferation. Increased cell cycling and a shift in cell cycle distribution to more cells in G1 was observed at stage II of leukemogenesis (50 to 60 days postinjection), at which time a clonally expanded cell population is known to emerge in thymuses of injected mice. Acridine orange staining resolved these novel cycling cells from subpopulations of normal thymic lymphoblasts on the basis of intermediate RNA content. The transition from stage II to stage III (50 to 60 days postinjection) was accompanied by the outgrowth of a major cycling population with a distinct, often increased, RNA content. As a result, the residual "normal" background of cycling cells often observed in stage II was markedly reduced or completely absent by stage III. Populations of cycling blasts from mice with frank leukemia differed from those at stage III by a variability in mean RNA content and in cell cycle distribution indicative of individual tumor heterogeneity. In addition, thymomas often contained multiple populations of cycling blasts that could be resolved by their discrete RNA distributions. Simultaneous staining of DNA and RNA by acridine orange appears particularly well-suited for studying a heterogeneous population of cycling and noncycling cells represented by mouse thymus. This method has permitted a rapid and quantitative analysis of cell cycle parameters at progressive stages of viral leukemogenesis in AKR mice.
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PMID:Changes in thymocyte proliferation at different stages of viral leukemogenesis in AKR mice. 241 23

Ditercalinium (DIT; NSC 335153), a 7H-pyridocarbazole dimer, was reported to be capable of binding with high affinity to DNA by bisintercalation. Both the cytostatic and cytotoxic effects of this drug have been attributed to its binding to DNA. DIT inhibits the growth and is cytotoxic to Friend erythroleukemia (FL) cells. When FL cells were treated with 0.5-2.5 microM DIT and then stained with acridine orange (AO), which differentially stains DNA and RNA, the green, orthochromatic fluorescence representing AO binding to DNA was unchanged, while the metachromatic red luminescence characteristic of AO binding to RNA was reduced by as much as 40% in 4 hr; the effect was DIT-concentration dependent. The reduction in RNA stainability by DIT in the absence of any significant decrease in RNA content, was also observed with another RNA-specific fluorochrome, pyronin Y (PY). These results indicate that in live cells DIT preferentially binds to RNA rather than DNA, preventing stainability of the former by the monointercalating dyes AO and PY. When FL cells were exposed to 10 microM DIT after being first permeabilized by ethanol, the subsequent stainability of DNA in these cells was reduced by up to 67% and RNA by up to 44%, indicating that under these conditions DIT binds to both DNA and RNA. This observation was confirmed by competition experiments between AO and DIT bound to DNA or RNA in permeabilized cells mixed with equivalent numbers of RNA-containing (DNase-treated) or DNA-containing (RNase-treated) cells, respectively. The mechanisms that protect DNA against binding by DIT in live cells are unknown but are lost in fixed cells and may be related to maintenance of cellular and/or nuclear membrane integrity. If the propensity for other intercalating drugs to bind to RNA in live cells is correlated with their antitumor activity as is DIT, the rationale for designing new drugs based solely on their affinity for DNA should be reevaluated.
Leukemia 1989 Jul
PMID:The antitumor intercalating drug ditercalinium binds preferentially to RNA in Friend erythroleukemia cells. 247 3

A new cytotoxic acridine alkaloid that exhibited antitumor activity in vivo was isolated from a marine Dercitus species sponge collected at a depth of 160 m in the Bahamas. This violet alkaloid, designated dercitin, inhibited the proliferation of cultured murine and human leukemia, lung, and colon tumor cells at nM concentrations (IC50 values of 63-150 nM) and prolonged the life of mice bearing ascitic P388 tumors (%T/C = 170, 5 mg/kg, i.p., QD1-9). Dercitin was also active against i.p. B16 melanoma and modestly inhibited the growth of s.c. Lewis lung carcinoma on the same schedule. DNA blocked the antiproliferative effects of the agent in culture, and incorporation studies indicated that dercitin disrupted DNA and RNA synthesis with less effects on protein synthesis, similar to the effects of known DNA intercalators. After 1-h exposure to 400 nM dercitin, the rates of incorporation of [3H]uridine, [3H]thymidine, and [3H]leucine by cultured P388 cells were inhibited 83, 61, and 23%, respectively. Equilibrium dialysis indicated that dercitin bound calf thymus DNA with an affinity of 3.1 microM and maximal binding of 0.20 mol dercitin/mol base pair. Binding involved intercalation as evidenced by ability to relax supercoiled phi X174 DNA (half maximal concentration for dercitin relaxation was 36 nM). The effects of dercitin on DNA mobility were reversible, and complete relaxation of DNA with topoisomerase I in the presence of dercitin followed by phenol extraction resulted in the appearance of supercoiled DNA. Dercitin, at microM concentrations, had a small effect in the K+-sodium dodecyl sulfate assay using cultured P388 cells, suggesting minimal inhibition of topoisomerase activity. But, dercitin completely inhibited DNA polymerase I/DNase nick translation of DNA at 1 microM. Relaxation of DNA at a given concentration was greater than inhibition of nick translation suggesting that the effects of dercitin on enzyme activity were secondary to changes in DNA conformation. Results indicate that dercitin is a new marine natural product that probably exerts its biological effects through intercalation into nucleic acids.
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PMID:Antitumor activity and nucleic acid binding properties of dercitin, a new acridine alkaloid isolated from a marine Dercitus species sponge. 254 17

HL-60/AMSA is a human leukemia cell line that is 100 times more resistant to the cytotoxic actions of the antineoplastic, topoisomerase II-reactive DNA intercalating acridine derivative amsacrine (m-AMSA) than is its parent HL-60 line. HL-60/AMSA cells are minimally resistant to etoposide, a topoisomerase II-reactive drug that does not intercalate. Previously we showed that HL-60 topoisomerase II activity in cells, nuclei, or nuclear extracts was sensitive to m-AMSA and etoposide, while HL-60/AMSA topoisomerase II was resistant to m-AMSA but sensitive to etoposide. Now we show that purified topoisomerase II from the two cell lines exhibits the same drug sensitivity or resistance as that in the nuclear extracts although the magnitude of the m-AMSA resistance of HL-60/AMSA topoisomerase II in vitro is not as great as the resistance of the intact HL-60/AMSA cells. In addition HL-60/AMSA cells are cross-resistant to topoisomerase II-reactive intercalators from the anthracycline and ellipticine families and the pattern of sensitivity or resistance to the cytotoxic actions of the various topoisomerase II-reactive drugs is paralleled by topoisomerase II-reactive drug-induced DNA cleavage and protein cross-link production in cells and the production of drug-induced, topoisomerase II-mediated DNA cleavage and protein cross-linking in isolated biochemical systems. In addition to its lowered sensitivity to intercalators, HL-60/AMSA differed from HL-60 in 1) the susceptibility of its topoisomerase II to stimulation of DNA topoisomerase II complex formation by ATP, 2) the catalytic activity of its topoisomerase II in an ionic environment chosen to reproduce the environment found within the living cell, and 3) the observed restriction enzyme pattern on a Southern blot probed with a cDNA for human topoisomerase II. These data indicate that an m-AMSA-resistant form of topoisomerase II contributes to the resistance of HL-60/AMSA to m-AMSA and to other topoisomerase II-reactive DNA intercalating agents. The drug resistance is associated with additional biochemical and molecular alterations that may be important determinants of cellular sensitivity or resistance to topoisomerase II-reactive drugs.
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PMID:Characterization of an amsacrine-resistant line of human leukemia cells. Evidence for a drug-resistant form of topoisomerase II. 255 Apr 42

Ledakrin [1-nitro-9-(3'-dimethylamino-N-propylamino)acridine], an antitumor drug of the 1-nitro-9-aminoacridine family, was able to induce DNA-protein crosslinks in intact L1210 leukemia cells, as demonstrated by the potassium-dodecyl sulfate precipitation technique. Ledakrin-induced DNA-protein crosslinks were not readily reversible nor were they accompanied by DNA double-strand breaks. Also, ledakrin produced virtually no crosslinks in isolated nuclei. Ledakrin-induced DNA-protein crosslinks seemed not to be mediated by topoisomerase II, unlike well-established effects of a chemically related antitumor drug, 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA). Four ledakrin analogs of divergent cytotoxic potencies also induced DNA-protein crosslinks but not DNA double-strand breaks in intact L1210 cells. A significant positive correlation existed between the ability of ledakrin and its 1-nitro analogs to induced DNA-protein crosslinks and the antiproliferative effects of these drugs. The results are consistent with the previously shown ability of 1-nitro-9-aminoacridines to covalently bind to macromolecules after metabolic activation in the cell. In addition to previously demonstrated DNA interstrand crosslinks and monofunctional adducts, DNA-protein crosslinks constitute another type of DNA lesion induced by 1-nitro-9-aminoacridines.
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PMID:Induction of DNA-protein crosslinks by antitumor 1-nitro-9-aminoacridines in L1210 leukemia cells. 255 39

The effect of three acridine derivatives, 9-aminoacridine (9AA), 4'-(9-acridinylamino)-methanesulphon-O-anisidide (O-AMSA) and quinacrine were compared in their ability to protect against the cytotoxicity of amsacrine, 9-[[2-methoxy-4-[(methylsulfonyl)amino]phenyl]amino)-N,5-dimethyl-4- acridine-carboxamide (CI-921), N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (AC), etoposide, mitoxantrone and doxorubicin. Cytotoxicity was measured in vitro by clonogenic survival assay and in vivo by life extension assays. All three acridine derivatives protected a Lewis lung cell line in vitro against CI-921, with 9AA having the highest activity. Cellular uptake of [14C] CI-921 by cultured Lewis lung cells was unaffected by 9AA, and slightly stimulated by O-AMSA and quinacrine. 9AA protected Lewis lung cells in vitro against the cytotoxicity of amsacrine, CI-921, AC and etoposide, partially against mitoxantrone but not against doxorubicin. A similar result was obtained with the human melanoma cell line MM96, where 9AA protected against CI-921 but not against doxorubicin toxicity. 9AA protected P388 leukaemia in vivo against amsacrine, CI-921 and AC cytotoxicity, partially against etoposide but not against mitoxantrone or doxorubicin. 9AA also protected against animal toxicity caused by high dose amsacrine and partially against CI-921 toxicity. It is hypothesized that DNA intercalating chemoprotectors act by restricting the conformational flexibility of the DNA and thus the ability of topoisomerase II to form a 'cleavable complex' in which the DNA is covalently linked to the enzyme.
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PMID:Chemoprotection by 9-aminoacridine derivatives against the cytotoxicity of topoisomerase II-directed drugs. 256 Oct 99

Amsacrine, an acridine derivative used clinically in the treatment of acute leukaemia, has formed the basis for the development of further compounds with high activity against experimental solid tumours, one of which is currently in clinical trial. We have compared the ability of these drugs to cause point mutations in bacteria, 'petite' mutations in yeast and mutations in mammalian cells. Several of the compounds are frameshift mutagens in Salmonella typhimurium TA1537 while some cause 'petite' mutagenesis in Saccharomyces cerevisiae. All are highly clastogenic and have significant mutagenic activity at the 6-thioguanine locus in cultured V79 Chinese hamster fibroblasts following 1 h drug exposures. None are mutagenic at the ouabain locus of these cells. The relationship between different indicators of mutagenicity has been studied using an additional set of amsacrine analogues, some of which are mutagenic in S. typhimurium TA98. There is a highly significant relationship between mutation frequency (measured as resistance to 6-thioguanine) and either cytotoxicity (D37 values in a clonogenic assay) or clastogenicity (ability to induce micronuclei). However, there is no correlation with mutagenicity in microbial systems. The results suggest that the cytotoxicity, clastogenicity and mutagenic activity of the amsacrine analogues is mediated by similar mechanisms, probably involving the enzyme DNA topoisomerase II.
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PMID:Mutagenicity profiles of newer amsacrine analogues with activity against solid tumours: comparison of microbial and mammalian systems. 264 76

A new method for immunophenotyping of cells in suspension has been developed. The method is based on identification of cells that have formed rosettes with superparamagnetic particles (Dynabeads) conjugated with monoclonal antibodies directed against cell-surface antigens. The method is extremely simple. Twenty-five microliters of cells are mixed with 5 microliters of Dynabeads in U-bottom microtitre wells. Following a 1-min centrifugation step, rosette formation can be inspected in the microscope. Staining of the cells before rosetting with acridine orange/ethidium bromide allows direct quantification of viable cells carrying a given marker. The method is limited to detection of cell-surface antigens, and the results obtained are comparable to those seen with indirect immunofluorescence. The method may be used for phenotyping of leukaemia and other cancer cells, and can also be used for phenotyping of cells that can only be obtained in small numbers, such as spinal fluid cells.
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PMID:Rapid immunomagnetic phenotyping of cells. 268 87

Several new cytostatic drugs have entered clinical Phase I-II studies for treatment of leukemia: most promising are pyrimidine analogues such as 5-Azacytosine arabinoside, 5-Aza-2-deoxycytidine, 5-Azacytidine, cyclocytidine, and 2'-2'-difluorodeoxycytidine. They act on different biochemical levels towards DNA-synthesis. Fludarabine is a purin analogue and seems very active in treating CLL. Tiazofurin is an antimetabolite counter-acting nicotinic acid with most promising activity in CML blast crisis. Other substances include deoxycoformycin, an adenosine analogue for treatment of T-cell neoplasias, 1, 25-dihydroxy vitamin D 3 as differentiation inducer, and homoharringtonine, an alkylating agent widely used for treating de novo AML in China. New anthracyclines are THP-adriamycin, fluoroadriamycin, and 4-demethoxydaunorubicin. Amsacrine (mAMSA) finally, is a synthetic aminoacridine with DNA-intercalating properties. The intact acridine ring appears essential for antitumor activity. The plasma clearance of both total amsacrine and unchanged parent species is biphasic. There is a considerable influence of hepatic and renal impairment on plasma clearance. Clinical toxicities include marked myelosuppression, gastrointestinal symptomes, phlebitis, mucocutaneous lesions, occasionally alopecia and neurotoxities. It is a very active drug, particularly in treating AML. Studies using mAMSA alone or in combination revealed comparable results to the anthracyclines. The E.O.R.T.C. Leukemia Cooperative Group has used successfully mAMSA in several trials: relapsed and refractory AML, intensive maintenance treatment during first remission in AML, and, still on-going, during intensive consolidation randomized against BMT in AML-patients under the age of 45 years, and randomized against standard consolidation between the age of 45 and 60 years.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:New drugs in the treatment of acute and chronic leukaemia: current role of mAMSA. 269 2


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