Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: UMLS:C0023467 (acute myeloid leukemia)
35,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A 59-year-old female suffering from malignant lymphoma developed therapy-related acute myeloblastic leukemia (t-AML) after chemotherapy consisting of treatment with DNA-topoisomerase II inhibitors, etoposide and mitoxantrone, and an alkylating agent, cyclophosphamide. The cumulative dose of etoposide administration was 5500 mg; 1500 mg given intravenously and 4000 mg orally. One year later, she suddenly developed AML of FAB M2. Cytogenetic analysis of bone marrow cells revealed deletion of 7q and a rare translocation, t(16;21)(q24;q22). Southern blot analysis of bone marrow cells did not detect rearrangement of the AML1 gene, however, fluorescence in situ hybridization (FISH) analysis of bone marrow cells at interphase and metaphase revealed a translocational splitting between chromosome 21 involving AML1 gene and chromosome 16. These results suggest that the breakpoint is not located in the breakpoint cluster region for t(8;21). The patient was treated with chemotherapy and entered complete remission.
...
PMID:A case of therapy-related acute myeloblastic leukemia with t(16;21)(q24;q22) after chemotherapy with DNA-topoisomerase II inhibitors, etoposide and mitoxantrone, and the alkylating agent, cyclophosphamide. 963 85

Caspases are aspartate-specific cysteine proteases that play a pivotal role in drug-induced cell death. We designed RT-PCR assays to analyse the expression of CASP-3, CASP-4, CASP-6 and the long and short isoforms of CASP-2 genes in human cells. These genes heterogeneously coexpress in leukemic cell lines and bone marrow samples from patients with de novo acute myelogenous leukemia at diagnosis. Treatment of U937 and HL60 leukemic cells and HT29 colon carcinoma cells with the topoisomerase II inhibitor etoposide upregulates CASP-2 and CASP-3 genes in these cells before inducing their apoptosis. This effect of etoposide is not observed in K562 cells and bcl-2-transfected U937 cells which are less sensitive to drug-induced apoptosis. Nuclear run-on experiments demonstrate that etoposide increases CASP gene transcription in U937 cells, an effect that is prevented by Bcl-2 overexpression. Upregulation of CASP genes is associated with an enhanced synthesis of related procaspases that precedes the appearance of apoptosis markers including caspase-3 activation, poly(ADP-ribose) polymerase cleavage and internucleosomal DNA fragmentation. These results suggest that the ability of tumor cells to upregulate CASP-2 and CASP-3 genes in response to cytotoxic drugs could be predictive of their sensitivity to drug-induced apoptosis.
...
PMID:Upregulation of CASP genes in human tumor cells undergoing etoposide-induced apoptosis. 967 9

The myelodysplastic syndromes (MDS) are a heterogeneous group of disorders with an invariably fatal outcome. Other than bone marrow transplantation, no treatment has been able to alter the natural history of MDS. As a result, there has been an interest in identifying new and more effective chemotherapeutic agents. Many of the drugs that have been evaluated in an attempt to increase remissions and prolong survival were selected because of their activity in acute myeloid leukemia. Thus cytarabine has been the most widely studied drug. Although numerous studies suggested activity for low-dose cytarabine (LoDAC), a careful analysis of the data identified a complete remission (CR) rate of less than 20%, without meaningful clinical benefit. The issue of LoDAC was finally put to rest by a randomized trial in which survival was no better than with supportive care. 5-Azacytidine induces cellular differentiation by hypomethylation of DNA. Phase II trials noted CRs in fewer than 10% of patients, with response rates under 30%, although additional patients appeared to experience hematologic and clinical benefit. A randomized trial of 5-azacytidine versus supportive care failed to demonstrate a survival benefit. One of the most promising new agents is the topoisomerase inhibitor topotecan, which achieves CRs in more than 30% of patients. Combinations of this drug with other active agents are in development. Obviously, new treatment strategies are needed to improve the outcome of MDS patients. Combination approaches incorporating new, active agents should have sound scientific rationale, targeting biological differences among the various MDS subtypes.
...
PMID:Standard and low-dose chemotherapy for the treatment of myelodysplastic syndromes. 973 95

The treatment of cancer with alkylating drugs or topoisomerase II inhibitors can be responsible for the development of myelodysplastic syndromes and acute myelogenous leukemia. Alkylating agents such as melphalan and cisplatinum mainly produce damages at chromosomes 5 and 7 whereas topoisomerase II inhibitors-induced lesions essentially affect chromosomes 11 and 21. Rearrangements of the MLL gene at band 11q23 are frequently observed in human de novo myeloid and lymphoid leukemia as well as in leukemia or myelodysplasia secondary to therapy with drugs targetting topoisomerase II such as the epipodophyllotoxins. A relationship between the treatment with etoposide on teniposide and the development of translocations of the MLL gene has been clearly evidenced. The potential molecular basis of the chromosomal rearrangements implicating topoisomerase II and its inhibitors are discussed. The chemical structure of the inhibitors, their mechanism of action and the genes targetted by these drugs are presented. DNA cleavages induced directly by topoisomerase II inhibitors or by the drug induced apoptotic cellular response are responsible for nonrandom chromosomal aberrations and contribute to leukemogenesis.
...
PMID:[Chromosome translocations and leukemias induced by inhibitors of topoisomerase II anticarcinogenic drugs]. 975 16

CBFA2(AML1) has emerged as a gene critical in hematopoiesis; its protein product forms the DNA-binding subunit of the heterodimeric core-binding factor (CBF) that binds to the transcriptional regulatory regions of genes, some of which are active specifically in hematopoiesis. CBFA2 forms a fusion gene with ETO and MDS1/EVI1 in translocations in myeloid leukemia and with ETV6(TEL) in the t(12;21) common in childhood pre-B acute lymphoblastic leukemia. We have analyzed samples from 30 leukemia patients who had chromosome rearrangements involving 21q22 by using fluorescence in situ hybridization (FISH). Our analysis showed that 7 of them involved CBFA2 and new translocation partners. Two patients had a t(17;21)(q11.2;q22), whereas the other 5 had translocations involving 1p36, 5q13, 12q24, 14q22, or 15q22. Five of these novel breakpoints in CBFA2 occurred in intron 6; this same intron is involved in the t(3;21). One breakpoint mapped to the t(8;21) breakpoint region in intron 5, and 1 mapped 5' to that region. All 7 CBFA2 rearrangements resulted from balanced translocations. All 7 patients had myeloid disorders (acute myeloid leukemia or myelodysplastic syndrome); 2 were de novo and 5 had treatment histories that included topoisomerase II targeting agents. The association of therapy-related disorders with translocations involving CBFA2 was significant by Fisher's exact test (P < .003). These results provide further evidence that this region of CBFA2 is susceptible to breakage in cells exposed to topoisomerase II inhibitors.
...
PMID:CBFA2(AML1) translocations with novel partner chromosomes in myeloid leukemias: association with prior therapy. 976 73

Despite progress in leukemia therapy, only 20-30% of patients with acute myelogenous leukemia (AML) are cured. 1-beta-D-arabinofuranosylcytosine- and topoisomerase II-reactive drugs are the primary therapeutic agents used. The aim of this study was to evaluate the potential activity of tallimustine in leukemia. In this study, we first investigated the efficacy and toxic effects of tallimustine, a distamycin-A derivative, in a human leukemia model in severe combined immunodeficient (SCID) mice. On the basis of its dramatic activity in this preclinical study, a Phase I study of tallimustine at a starting dose of 300 microgram/m2/day for 3 days every 3-4 weeks was conducted in patients with refractory or relapsed leukemia. In SCID mice grafted with a human myelomonocytic leukemia cell line, tallimustine resulted in complete remission of disease in most mice at tolerable dosages ranging from 0.86 to 3.0 mg/kg/day for 3 days and was combined effectively and safely with a 2-day schedule of high-dose ara-C. In the Phase I study, 26 patients with refractory or relapsed leukemia were treated. The maximum tolerated dose was 900 microgram/m2/day for 3 days every 3-4 weeks. This dose was 3 times higher than the maximum tolerated dose in solid tumors and was limited by severe mucositis. Magnesium and potassium wasting were also observed, but other side effects (fatigue and gastrointestinal) were minor. Two (8%) patients with AML achieved complete remission and two achieved hematological improvement with persistent thrombocytopenia. The results of this study indicate that tallimustine has promising activity in AML. Future studies may combine tallimustine with other agents known to be active against AML, and investigate its activity in other hematological malignancies. The recommended Phase II single-agent dose of tallimustine is 750-900 microgram/m2/day for 3 days, and combination studies may start at 50-66% of this dose schedule. The SCID mouse model of human leukemia may be promising in the preclinical evaluation and selection of potential antileukemic agents.
...
PMID:Tallimustine, an effective antileukemic agent in a severe combined immunodeficient mouse model of adult myelogenous leukemia, induces remissions in a phase I study. 981 37

Phenotypic conversion from acute myeloid leukemia (AML) to acute lymphoblastic leukemia (ALL) is rare. A 38-year-old man was initially diagnosed as having AML (FAB-M2) associated with the t(8;21)(q22;q22) chromosomal abnormality. The blasts showed myeloperoxidase (MPO) activity and CD13 antigen expression. He showed complete remission after standard chemotherapy for AML. However, the patient relapsed with blasts showing ALL morphology (FAB-L1), MPO negativity, and CD19 antigen expression 33 months after cessation of AML therapy. Cytogenetic analysis at relapse was unsuccessful. Molecular analysis of ALL blasts revealed immunoglobulin heavy-chain gene and MLL gene rearrangements but no AML1 gene. MLL gene rearrangement or the 11q23 chromosomal abnormality has been associated with therapy-related leukemia. The subsequent ALL in our patient may have been induced by the chemotherapy including daunorubicin, known as a topoisomerase II inhibitor.
...
PMID:Phenotypic conversion from t(8;21) acute myeloid leukemia to MLL gene rearrangement-positive acute lymphoblastic leukemia. 984 25

The t(9;11)(p22;q23) is the most common chromosomal translocation in topoisomerase II inhibitor therapy-related acute myeloid leukemia (tAML). This translocation fuses the MLL and AF9 proto-oncogenes producing a novel chimeric protein. In order to gain insight into the mechanism generating the t(9;11) and to clarify the role topoisomerase II inhibition may play in that mechanism we have cloned and sequenced the breakpoints from four tAML patients with the t(9;11). This sequence analysis identifies topoisomerase II consensus binding sequences near or at the chromosome 11 and chromosome 9 breakpoints in all four patients. One patient also had the consensus binding sequence for the TRANSLIN DNA-binding protein at the 9p22 and 11q23 breakpoints. Our results further support a direct role for topoisomerase II in the genesis of these tAML translocations.
...
PMID:Cloning and sequence analysis of four t(9;11) therapy-related leukemia breakpoints. 984 20

Acute myelogenous leukemia (AML) represents 80% of adult acute leukemias. A standard-dose chemotherapy allows to obtain 52% to 72% of complete remission (CR). A major limitation for success in chemotherapy of AML is dominance of drug-resistant subpopulations of cells. Cytosine-arabinoside (Ara-C) is a basic drug in AML treatment. Myeloblasts resistance to Ara-C could be kinetic or pharmacological. The classical multidrug resistance (MDR) depends on presence in resistant myeloblasts ATP-dependent drug-efflux pump with ability to remove cytotoxic drugs from the cells. It is a product of MDR1 gene called P-glycoprotein (Pgp). Pgp is responsible for cell resistance to cytotoxic compounds of natural origin, such as anthracyclines, vinca alkaloids, epipodophyllotoxins, taxanes, colchicine and amsacrine. There were also identified not Pgp-dependent multidrug resistance mechanisms (non-Pgp MDR) in AML. All mentioned above drugs are involved but not taxol. Non-Pgp MDR depends on topoisomerase II alfa activity alterations, multidrug resistance-associated protein (MRP) expression and lung resistance-related protein (LRP) expression. Pgp positive AML patients have poorer complete remission (CR) rate, decreased remission duration and overall survival. Pgp expression is detected among 70% AML patients older than 55. The most promising drugs in circumventing classical MDR seems cyclosporin A (CsA) and cyclosporin D (SDZ PCS 833). They are successfully used in refractory and relapsed AML.
...
PMID:[The causes of treatment ineffectiveness in acute myelogenous leukemia--the role of blast resistance to cytotoxic drugs]. 1002 86

Two main types of therapy-related acute myeloid leukemias (tAML) and myelodysplastic syndromes (tMDS) have been described. The first classical type typically occurs late after use of alkylating agents and presents as MDS with -7/del 7q and/or -5/del5q. The second form occurs early after the use of agents targeted at topoisomerase II, and presents as AML with 11q23 or other rearrangements of de novo AML. Recently, we and others reported, in AML and MDS, a strong correlation between cytogenetic rearrangements leading to 17p deletion, a specific type of dysgranulopoiesis and p53 mutation; several of those cases of 17p- syndrome were therapy-related. Over the last 15 years, we observed 25 cases of tAML and tMDS with 17p deletion, which represented 36% of the AML and MDS with 17p deletion diagnosed during that period. Median age was 59 years. Twenty-one patients had tMDS and four tAML. Typical dysgranulopoiesis and p53 mutation and/or overexpression were seen in 22 of 24 and 16 of 19 evaluable patients, respectively. 17p deletion resulted from unbalanced translocations involving 17p (18 cases), monosomy 17 (five cases), i(17q) (one case) or del 17p (one case). Twenty-one patients also had -5/del 5q, and/or -7/del 7q. Median interval from treatment of the first tumor of tAML and tMDS was 94 months (range 19-252). Median survival was only 7 months. Based on primary tumor and antineoplastic agents used, patients could be relatively well divided into two groups: a first group of 11 cases, occurring mainly after a lymphoid neoplasm (eight cases) treated by chemotherapy with an alkylating agent (10 cases), and a second group of 14 cases occurring after essential thrombocythemia (ET) or polycythemia vera (PV) treated mainly by hydroxyurea (10 cases), pipobroman (eight cases), 32P (six cases) but rarely by alkylating agents (two cases). -7/del 7q was found in 10 of the 11 patients in the first group, as compared to three of the 14 patients of the second group (P = 0.0001). Therefore, therapy-related cases represent a high proportion of AML and MDS with the 17p- syndrome. They have many features in common with classical tMDS and tAML, including long interval from the first tumor, a usual preleukemic phase, and frequent occurrence of -5/del 5q. About one half of them, in addition, occur after alkylating agents and generally carry -7/del 7q. The other half, however, occur mainly after ET or PV treated by hydroxyurea or other non-alkylating agents, and usually have no -7/del 7q. These findings bring further support to a possible relationship between prior drugs used and cytogenetic rearrangements in tAML and tMDS.
...
PMID:Therapy-related myelodysplastic syndrome and acute myeloid leukemia with 17p deletion. A report on 25 cases. 1002 99


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---