Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A case of chronic myelogenous leukemia (CML) with complex chromosomal abnormalities is reported. Conventional staining techniques indicated incorrectly that the Ph1 chromosome was not present. These studies showed a 46,XY,-1,+C karyotype in all bone marrow cells. Employing RFA (R bands by fluorescence using acridine orange) technique it was clear that the part of the long arm of chromosome 1 (1q23 leads to qter) was missing the tip of the long arm chromosome 22 (band q22) was translocated to it. The missing long arm of chromosome 1 was translocated to the long arm of chromosome 9. Furthermore, there was a break at band 9q22 and the whole terminal part was lost. The value of RFA technique is discussed.
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PMID:The value of reverse banding in detecting bone marrow chromosomal abnormalities: translocation between chromosomes 1, 9, and 22 in a case of chronic myelogenous leukemia (CML). 27 21

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

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

Many of the conceptual advances in the treatment of advanced cancer have resulted from studies of the hematologic malignancies: The signal importance of complete remission, the complete disappearance of evident disease, as the major contributor to significant palliation; the first studies of adjuvant therapy, that is chemotherapy given to patients free of disease, which demonstrated prolongation of disease-free periods; the first studies of intensification, including early, intermittent, and late; combination chemotherapy; and finally, the important observation that advanced metastatic malignancies can be cured were made in studies of these important diseases. Because of treatment advances that have occurred over the last 10 to 20 years, the majority of patients with adult hematologic malignancies that were once considered universally fatal can be either cured or have substantial palliation. Treatment for adult acute leukemia has advanced such that 15% to 20% of patients have prolonged disease and treatment-free survivorship; in Hodgkin's disease, over 70% of patients can be cured; and for the lymphomas, the majority or 50% to 60% of patients can be cured with available treatments. Major treatment advances in supportive treatment such as allogeneic transfusion and allogeneic and autologous bone marrow transplantation improve the perspective for control of the hematologic malignancies. In addition, the potential for biologic response modifiers or the biologic products of normal cells that are normally involved in the regulation of both proliferation and differentiation show enormous potential for the treatment of advanced disease. Studies of interferon have shown promising early results in chronic granulocytic leukemia and in hairy cell leukemia. A new class of drugs, the acridine analogs, of which AMSA (4'-[9-acridinylamino]methanesulfon-M-anisidide) is a member, has been introduced and has established activity against acute leukemia. VP-16 (etoposide) has just become commercially available and is an important drug both in leukemia and lymphoma. Finally, the discovery of new knowledge about the biochemical pharmacology of drugs such as arabinosyl cytosine has offered a major advance in salvage treatment and the potential for substantial further improvement in the frontline management of these diseases. The rapid advances in both palliative and curative treatment for the hematologic malignancies have generally found broad application to the management of advanced cancer arising from other organ systems.
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PMID:The hematologic malignancies. Leukemia, lymphoma, and myeloma. 620 91

AMSA, an acridine derivative with significant antitumor activity in experimental tumors, was administered to 17 patients with advanced tumors refractory to standard chemotherapies. A phase I study was undertaken in 10 patients with solid tumors and lymphomas. Dose-limiting toxicity was myelosuppression. With a median dose of 90 mg/m2 (75-148 mg/m2), median lowest WBC count was 1,000/mm3 (100-3,200) on day 11 and its recovery up to 4,000/mm3 was seen on day 21, while lowest platelet count was 42 X 10(3)/mm3 (7-300 X 10(3) on day 12 and its recovery up to 100 X 10(3)/mm3 was on day 20. Non-hematological toxicities were nausea (39%), vomiting (11%) and phlebitis (17%) in 18 courses of therapy. The result indicated that the recommended dose schedule for a phase II evaluation was 90 mg/m2, every three weeks. Therapeutic activity was observed in patients with non-Hodgkin's lymphoma (one partial response and two minor responses out of four). Two out of five breast, one ovarian, and one melanoma patients showed stable diseases. Five leukemic patients (three AMLs, one MoL, and one blastic CML) were treated with AMSA, and in these cases cytoreduction of peripheral and bone marrow blasts was seen, but it was not adequate to induce remission. Further clinical trials with this agent are warranted, especially in patients with acute leukemia, lymphoma and breast cancer.
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PMID:[Phase I-II studies of a new antineoplastic agent, 4'-(9-acridinylamino)-methanesulfon-m-anisidide (AMSA)]. 689 58

A newly developed flow cytometry technique for simultaneous measurements of three features of individual cells--DNA, RNA, and nuclear diameter--using acridine orange as a fluorescent metachromatic dye, has been applied to cell-cycle analysis. DNA stemline determination, and to classification of 102 cases of human leukemias in adults. Acute lymphoblastic leukemia (L1-2) was characterized by moderately increased RNA of G0/1 cells as compared to normal lymphocytes; acute nonlymphoblastic leukemia (M 1-5) by very high RNA of G0/G1 cells. Both had either diploid or aneuploid DNA stemlines. Chronic lymphocytic leukemia showed diploid DNA, very low proliferation, and low RNA, similar to that found by use to be typical for normal B cells. In chronic myelogenous leukemia, two cell populations were distinguished, one with high RNA, the other with very low RNA and elongated nuclear diameter due to stripped, unfolded nuclei of polymorphonuclear leukocytes. The number of leukemic blast cells, identified by aneuploid DNA values, correlates well with conventional microscopy counts and could be followed during the course of treatment. Thus, acridine orange flow cytometry can be used to discriminate subtypes of human leukemias, to determine cell cycle stages, and to detect and monitor aneuploid leukemia stemlines.
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PMID:Discrimination of human leukemia subtypes by flow cytometric analysis of cellular DNA and RNA. 692 6

Peroxyacetyl nitrate (PAN), an ubiquitous air pollutant, induced apoptosis in human leukemia HL-60, human chronic myelogenous leukemia K-562, and mouse monocyte-macrophage RAW 264.7 cell lines. In the HL 60 cells, characteristic apoptosis morphology could be observed 4 h after the cells were treated with 50 microM PAN. Exposure of HL-60 cells to increasing concentrations of PAN (from 1 microM to 100 microM) confirmed the concentration dependence of apoptosis as evidenced by DNA fragmentation in HL-60 cells, chromatin condensation by acridine-orange staining, and the appearance of the DNA apoptotic peak in flow cytometry. During apoptosis in HL-60 cells, 3-nitrotyrosine and 3,5-dinitrotyrosine were detected by high-performance liquid chromatography and liquid chromatography-mass spectrometry-mass spectrometry. We hypothesized that PAN might induce cell death in human leukemia cells by releasing peroxynitrite and other reactive oxygen species (ROS) such as superoxide and hydrogen peroxide. Moreover, exogenous superoxide dismutase promoted PAN-induced apoptosis, and in contrast, a combination of superoxide dismutase and catalase suppressed this apoptosis. We also hypothesize that the generation of ROS during PAN-induced apoptosis in HL-60 cells could activate stress-activated protein kinase/jun N-terminal kinase activity. The formation of H2O2 produced from the dismutation of PAN-elicited superoxide anion contributed to the apoptotic mechanism in HL-60 cells through ROS pathways. These findings suggested that induction of apoptosis by the air pollutant PAN might occur as a result of the release of ROS.
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PMID:Peroxyacetyl nitrate-induced apoptosis through generation of reactive oxygen species in HL-60 cells. 1041 Nov 46

The leukemogenic property of BCR-ABL in chronic myeloid leukemia (CML) is critically dependent on its protein tyrosine kinase activity. STI571 inhibits the BCR-ABL kinase activity, the growth and the viability of BCR-ABL expressing cells. In this study, we report the apoptotic effect of STI571 in combination with daunorubicin (DNR) on peripheral blood mononuclear cells from 11 CML patients and four BCR-ABL-positive cell lines: AR230, LAMA84, K562 and KCL22. Primary blast cells were identified by flow cytometry on the basis of their low CD45 expression. Nucleus fragmentation, exposure of phosphatidylserines and decrease in mitochondrial membrane potential were measured using acridine orange, FITC-annexin V and DiOC6(3), respectively, to evaluate apoptosis. On cell lines, the effect of DNR was negligible, whereas STI571 induced 10 to 35% of apoptosis in 18 h. STI571 sensitized AR230, LAMA84 and K562 cells to DNR when apoptosis was measured at the mitochondrial and membrane but not the nuclear levels. On CML blast cells, phosphatidyl serine exposure was significantly induced by both DNR and STI571 and was higher when these drugs were used in combination (P < 0.0003). However, the effects of this drug combination were only additive and no sensitization of blast cells to DNR by STI571 was observed. Interestingly, sensitization was evidenced in CML but not normal lymphocytes. These results suggest that other mechanisms additional to Bcr-Abl tyrosine kinase activity could be responsible for DNR resistance, and further investigations are needed to understand its origin.
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PMID:Resistance to daunorubicin-induced apoptosis is not completely reversed in CML blast cells by STI571. 1204 Apr 47

The synthesis and biological evaluation of a homologous series of conjugates (9-13) of 2,5-diaziridinylbenzoquinone (DZQ) and 9-carbonylacridine, a DNA intercalating moiety, via a polymethylene unit (n=2-6) are described. In addition, the non-acridine compound 14, analogous to compound 12, and the 5-methyl-DZQ derivatized conjugate 15, an analog of compound 10, were also prepared. Through a Comet assay, compounds 9-13 were shown to produce DNA interstrand cross-links at submicromolar concentrations, consistent with K562 leukemia cells accumulating in the G2/M stage in the cell cycle. The cytotoxicity of compounds 9-15 was examined using a MTT assay on several human cancer cell lines, including chronic myeloid leukemia K562, the non-small cell lung cancers H596 and H460, and colon carcinoma cells BE and HT29. H460 and HT29 are rich in DT-diaphorase (DTD), and H596 and BE cells have negligible amounts of functional DTD. Under continuous exposure of drugs, except to the non-aziridine compound 19b, the IC50 values of all other compounds were determined to be in the range of 0.3-11.3 nM. Compound 10, which has a propyl linker group, was subjected to in vivo studies. When BDF1 mice with established mouse mammary carcinoma were treated with compound 10 (2 mg/kg at day 1 and 5 mg/kg at day 7), a significant delay (9-10 days) in cancer growth was recorded when compared to untreated controls. Furthermore, administration of compound 10 to nu/nu BDF1 mice bearing human lung cancer H460 xenograft (1.5 mg/kg for 10 for five consecutive days from day 13 and 17) also showed a significant reduction in tumor growth compared to untreated controls. The half-life of compound 10 in the presence of five different peptidases (porcine esterase, carboxypeptidase A, B and Y, and pepsin) was determined to be between 30 and 60 h.
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PMID:Synthesis and biological evaluation of novel diaziridinylquinone-acridine conjugates. 1450 82

The effects of a novel kind of nitrogen heterocycle compound, which was synthesized in our laboratory previously, on human chronic myelogenous leukemia K562 cells were investigated. The morphological changes were observed by Acridine orange (AO) staining. The screened results through DNA fragmentation and the Annexin V-FITC/PI staining assay showed that compound 8 blocked cell cycles at G(1) phase which led to apoptosis. The increase of caspase-3, 8, and 9 was detected, indicating that both of death-receptor and mitochondria-pathways were activated. Compound 8 induced a biphasic alteration in mitochondrial membrane potential of K562 cells. A dramatic elevation of Ca(2+) was also observed. In addition, a transient increase of ROS was also involved in the process. This study showed that compound 8 might be a potential chemopreventive agent for chronic myelogenous leukemia. It would guide our future work to synthesize more compounds derived from compound 8, which might have better effect, and to determine the target protein. Moreover, it might also provide a background mechanism for the introduction of this new type of promising therapeutic agent.
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PMID:A novel kind of nitrogen heterocycle compound induces apoptosis of human chronic myelogenous leukemia K562 cells. 1646 24


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