Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023467 (acute myeloid leukemia)
 35,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the past five years, several groups have reported acute myeloid leukemia (AML) often monoblastic, as a complication of chemotherapy regimens including the epipodophyllotoxins, etoposide and teniposide. This syndrome is distinct clinically, pathologically and cytogenetically from classical therapy-related myelodysplasia and AML. There is also evidence that other topoisomerase II inhibitors, such as the intercalating agents (including doxorubicin, mitoxantrone, and actinomycin D) may be leukemogenic. Furthermore, there may be further interactions from concomitant topoisomerase II inhibitors and alkylating agents. Topoisomerase II inhibitors induce DNA cleavage and other chromosomal aberrations, including sister chromatid exchanges. These clastogenic abnormalities are not fully understood, and may be specific for each cytotoxic agent. Work is in progress to clone breakpoints such as the t(9;11) and t(8;21) and the use of the resultant DNA probes will enhance our understanding of the leukemogenic process. Given the potential diversity in patients with secondary leukemia, cytogenetic studies should be mandatory for both enhancing our knowledge base and guiding treatment in individual patients. Clinicians must also be wary of the leukemogenic potential of 'dose-intense' regimens including agents such as etoposide and doxorubicin.
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PMID:Therapy-related acute myeloid leukemia secondary to inhibitors of topoisomerase II: from the bedside to the target genes. 128 Apr 61

We report two cases of secondary acute lymphoblastic leukemia (ALL) with t (4;11) (q21;q23) translocation occurring after chemotherapy and radiotherapy for a prior cancer. Seven previously published cases of secondary ALL with t (4;11) (q21;q23) are also reviewed. Most patients had received a combination of topoisomerase II inhibitors (anthracyclines, mitoxantrone, or the epipodophillotoxin derivatives VP16 or VM26) and cyclophosphamide, which have also been implicated in the pathogenesis of secondary acute myeloid leukemia (AML) with 11q23 rearrangements. These observations give further support to the existence of a subgroup of secondary acute leukemias with cytogenetic findings "specific" for de novo ALL and AML, especially those with translocations involving the 11q23 region.
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PMID:Secondary acute lymphoblastic leukemia with t (4;11): report on two cases and review of the literature. 139 Nov 25

The t(4;11)(q21;q23) has been associated with marked lineage heterogeneity. Most of the reported cases were classified as acute lymphoblastic leukemia (ALL). The t(4;11) is one of the commonest specific chromosomal translocations in ALL, occurring in 2% of childhood and 5% of adult cases. In childhood ALL, this translocation is associated with female sex, age less than 1 year, hyperleukocytosis, CD10-/CD19+ B-precursor cell immunophenotype, and myeloid-associated antigen (CD15) expression. There also appears to be an age-related difference in treatment outcome. Adults had the worst prognosis, and children aged 1 to 9 years appeared to have a better outcome than infants or adolescents. Reported cases of acute myeloid leukemia (AML) or secondary leukemia with the t(4;11) have not been well characterized. It is intriguing that virtually all of the reported cases with secondary leukemia had received epipodophyllotoxins or doxorubicin, agents that affect topoisomerase II and are associated with secondary AML characterized by 11q23 abnormalities. Identification of the involved gene(s) in the t(4;11) will provide a molecular approach permitting more accurate classification of these cases.
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PMID:Acute leukemias with the t(4;11)(q21;q23). 147 45

Etoposide (VP16-213), a topoisomerase II inhibitor, has produced complete responses in 17% of previously treated patients with acute nonlymphocytic leukemia (ANLL) but has little activity in acute lymphoblastic leukemia. As salvage therapy for relapsed ANLL etoposide produces 28% complete responses in combination with amsacrine, 49% with 5-azacytidine, and 51% with anthracycline. It has been successfully combined with high-dose cytarabine as a salvage treatment. In a randomized trial in previously untreated patients with ANLL, etoposide significantly prolonged remission duration. Etoposide has been used to intensify postinduction therapy with or without bone marrow rescue, but its exact role in that setting has not been clarified. Because of its schedule dependency in other tumors, etoposide should be investigated using different schedules in ANLL.
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PMID:Etoposide in the treatment of leukemias. 149 26

Two different classes of therapy-related acute myeloid leukemia (t-AML) seem to emerge. One class follows therapy with alkylating agents, increases in frequency with age, often presents with myelodysplasia (MDS), responds poorly to chemotherapy, and shows monosomy 7(-7), monosomy 5(-5), or loss of various parts of the long arms of these chromosomes (5q- and 7q-). The other class is related to therapy with cytostatic drugs targeting at DNA-topoisomerase II, often presents with overt leukemia, responds more favorably to chemotherapy, and shows balanced chromosome aberrations, primarily translocations involving chromosome bands 11q23 and 21q22. These two classes of t-AML may have their counterparts in de-novo acute myeloid leukemia (de-novo AML).
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PMID:Two different classes of therapy-related and de-novo acute myeloid leukemia? 165 39

The effect of recombinant human granulocyte colony-stimulating factor (G-CSF) on DNA topoisomerase II (topo II) expression was studied in two human acute myelogenous leukemia cell lines, NKM-1 and NOMO-1, which express G-CSF receptor and proliferate in response to exogenous G-CSF. Northern blot analysis revealed that the level of topo II mRNA in 16-h stimulated cells in serum-free medium with G-CSF (10 ng/ml) was approximately 2-fold higher than that in cells without G-CSF. Enhanced topo II mRNA expression was detectable within 3 h after the addition of G-CSF. Topo II activity in crude nuclear extracts from 16-h G-CSF-stimulated cells was also found to be approximately 2-fold greater than that from unstimulated cells. According to in vitro cytotoxic assay, the sensitivity of G-CSF-stimulated cells to intercalating (daunorubicin) and nonintercalating (etoposide) topo II-targeting drugs increased significantly, whereas no enhancement of sensitivity was observed with an alkylating agent (4-hydroperoxycyclophosphamide). The augmented drug sensitivity observed was not due to the increased level of drug transport, as suggested by the similar extent of [3H]etoposide uptake between G-CSF-stimulated and unstimulated cells. By measuring the topo II mRNA and the cytotoxicity of the above mentioned drugs, we obtained essentially the same results in G-CSF-responsive leukemia cells isolated from three acute myeloblastic leukemia patients, as observed in the cultured cell lines. These findings strongly suggest that the sensitivity to "topo II-targeting drugs" could be augmented by exogenous G-CSF through elevated topo II activity in G-CSF-responsive leukemia cells.
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PMID:Enhanced expression of DNA topoisomerase II by recombinant human granulocyte colony-stimulating factor in human leukemia cells. 169 57

Among the cytostatic drugs only the alkylating agents have been firmly established as being leukaemogenic. This report describes 4 cases of acute myeloid leukaemia and 1 of myelodysplasia occurring in a cohort of 212 patients with germ-cell tumours treated with etoposide, cisplatin, and bleomycin. The mean cumulative risk of leukaemic complications was 4.7% (SE 2.3) 5.7 years after start of etoposide-containing chemotherapy, and, compared with the risk in the general population, the relative risk of overt leukaemia was 336 (95% CI 92-861). No leukaemias were detected in a previous cohort of 127 patients with germ-cell tumours treated with cisplatin, bleomycin, and vinblastine. The increased risk of leukaemia was most probably due to etoposide alone or in combination with cisplatin or bleomycin, since other published work has also not revealed an excess of leukaemias among patients with germ-cell tumours treated with only cisplatin, bleomycin, and vinblastine. The risk of leukaemia was dose related since all 5 patients with leukaemic complications were among the 82 who had received a cumulative dose of more than 2000 mg/m2 etoposide, whereas no leukaemias were observed among 130 patients who had received up to 2000 mg/m2 (p = 0.004). 3 of the leukaemic patients had balanced chromosome translocations affecting bands 11q23 and 21q22. These translocations, and perhaps also other balanced aberrations, seem to be characteristic of myelodysplasia and acute leukaemia occurring after therapy with cytostatic agents acting on DNA-topoisomerase II.
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PMID:Increased risk of myelodysplasia and leukaemia after etoposide, cisplatin, and bleomycin for germ-cell tumours. 168 78

We investigated m-AMSA or doxorubicin (Dx) induced DNA single-strand breaks (DNA-SSB) in myeloid leukemia cells obtained from 8 adult patients suffering from AML. Highly purified AML cells were stimulated to proliferate with the addition of the appropriate growth factor (GCT) and exposed to different concentrations of m-AMSA or Dx for 1 or 4 h, respectively. DNA-SSB were determined by alkaline elution techniques. Either the kinetics or the amounts of DNA-SSB caused by both topoisomerase II inhibitors were variable among different cases. By increasing m-AMSA concentrations there was a concomitant increase in DNA-SSB up to a plateau at the highest concentrations. Dx induced DNA-SSB followed a bell shape curve with a decrease in the number of breaks at the highest concentrations that was evident in most cases. The interindividual variability of Dx-induced DNA-SSB was not correlated with intracellular Dx concentrations as assessed by flow cytometry. No correlation was evident between the amount of DNA breaks induced by m-AMSA and that induced by Dx. These data suggest that AML cells derived from different patients are not necessarily cross-sensitive or cross-resistant to topoisomerase II inhibitors with different chemical structures such as amsacrine or anthracyclines.
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PMID:Doxorubicin and m-AMSA induced DNA damage in blast cells from AML patients. 199 42

Several new cytostatic drugs have entered clinical phase I-II studies for the treatment of leukemia: the most promising are pyrimidine analogs such as 5-aza-cytidine, 5-aza-2'-deoxycytidine, 5-aza-cytosine arabinoside, and 2',2'-difluorodeoxycytidine. Fludarabine, a fluorinated purine analog, appears to be active in CLL and multiple myeloma. Deoxycoformycin, an adenosine analog, showed good activity in the treatment of hairy cell leukemia and T-cell neoplasias. 2-chloro-deoxyadenosine has recently been introduced into the treatment of CLL and hairy-cell leukemia refractory to deoxycoformicin. Tiazofurin, an antimetabolite which interferes with nicotine-adenine-dinucleotide (NAD) metabolism, has been applied in CML blast crisis. Other agents include 13-cis retinoic acid and 1, 25-dihydroxy vitamin D3 as differentiation inducers, and homoharringtonine, an alkylating agent which is widely used for ANLL treatment in China. Among new anthracyclines, aclarubicin, idarubicin, THP-adriamycin and fluoro-adriamycin should be mentioned. Mitoxantrone, a substituted anthraquinone, has successfully been applied in the treatment of relapsed and refractory ANLL. Amsacrine (m-AMSA), finally, is a synthetic aminoacridine which intercalates into DNA and inhibits DNA topoisomerase II. m-AMSA is not cross-resistant to anthracyclines and has been particularly active in ANLL treatment. Studies using m-AMSA alone or in combination revealed comparable results to anthracycline--containing regimens. Cardiotoxicity of the anthracycline congestive type has not been observed with m-AMSA. The EORTC Leukemia Cooperative Group has successfully used m-AMSA in several trials prepositioning this drug stepwise: from relapsed and refractory ANLL, into intensive maintenance treatment during first remission in ANLL, and, still on-going, into intensive consolidation.
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PMID:New drugs in the treatment of acute and chronic leukemia with some emphasis on m-AMSA. 206 23

The present case, together with other reports reviewed herein, defines a new subtype of therapy-related acute myeloid leukemia (t-AML). This variant of t-AML is characterized by a short interval from initial drug therapy to bone marrow dysfunction and monocytic morphology without trilineage dysplasia. Unlike classic t-AML, which frequently has abnormalities of chromosomes 5 and/or 7, this new subtype is characterized by rearrangements involving band q23 of chromosome 11, most commonly a 9;11 translocation. The majority of patients with this subtype t-AML had prior cytotoxic therapy with topoisomerase II-reactive drugs including anthracyclines, epipodophyllotoxins, or actinomycin D, combined with either an alkylating agent or cisplatin. This association of prior therapy which includes topoisomerase II-reactive agents and a rapidly appearing t-AML involving the monocytic line and chromosome 11 requires additional study.
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PMID:Implication of prior treatment with drug combinations including inhibitors of topoisomerase II in therapy-related monocytic leukemia with a 9;11 translocation. 217 42


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