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)

The presumptive intracellular target of the anti-leukemia agents 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA) and 4-(4,6-O-ethylidene-beta-D-glucopyranoside) (VP-16) is the enzyme topoisomerase II. We found that 350 mM NaCl extracts of nuclei from HL-60 and HL-60/AMSA, an m-AMSA resistant HL-60 subline, contained equivalent topoisomerase II activity. However, the ability of m-AMSA to stimulate cleavage of exogenous DNA and to stimulate crosslinking of exogenous DNA with protein, processes which are topoisomerase II-mediated, was greatly reduced in the HL-60/AMSA extracts compared to the HL-60 extracts. HL-60 and HL-60/AMSA were almost equally sensitive to the cytotoxic effects of VP-16 and differences in VP-16-stimulated, topoisomerase II-mediated exogenous DNA cleavage and protein crosslinking between HL-60 and HL-60/AMSA extracts were much less than the differences in m-AMSA-stimulated exogenous DNA cleavage and protein crosslinking. Thus, the interaction between topoisomerase II activity, exogenous DNA, and m-AMSA or VP-16 indicated the susceptibility HL-60 and HL-60/ AMSA to the cytotoxic effects of the drugs. A similar correlation may exist in explanted leukemia cells from patients with acute myelogenous leukemia.
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PMID:The interaction between nuclear topoisomerase II activity from human leukemia cells, exogenous DNA, and 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA) or 4-(4,6-O-ethylidene-beta-D-glucopyranoside) (VP-16) indicates the sensitivity of the cells to the drugs. 303 64

The chemistry, pharmacology, pharmacokinetics, clinical efficacy, dosage and administration, and adverse effects of mitoxantrone are reviewed. Mitoxantrone, an aminoanthraquinone that was synthesized in 1979, belongs to a new chemical class of agents known as the anthracenediones. It possesses antiviral, antibacterial, immunomodulatory, and antitumor activity. The drug's antitumor activity is attributed to its interaction with DNA topoisomerase II, and its interaction with human cells may also involve nonintercalary, electrostatic interactions. Mitoxantrone is poorly absorbed orally and is most commonly administered intravenously. The drug is rapidly distributed into the red blood cells, white blood cells, and platelets, followed by deep-tissue sequestration. Mitoxantrone has demonstrated clinical efficacy in the treatment of leukemia, lymphoma, and breast cancer. As a single agent, mitoxantrone has a response rate of roughly 30% in acute nonlymphocytic leukemia or acute myeloid leukemia. In combination with other standard agents (cytarabine, vincristine, and prednisone), the response rate may reach 60%. In breast cancer, mitoxantrone's response rate as a single agent is 25-30%, while combination regimens produce response rates of 60% or more. The drug can cause cardiotoxicity with cumulative doses. Other adverse effects include myelosuppression, nausea and vomiting, stomatitis, mucositis, and alopecia. The cost of mitoxantrone is comparable to that of doxorubicin, but it is substantially more expensive than daunorubicin. Mitoxantrone is an important new agent with antitumor activity in leukemia, lymphoma, and breast cancer. In most situations, mitoxantrone will be considered second-line treatment or a restricted-use item because of its high cost and because of the lack of FDA approval for indications other than acute nonlymphocytic leukemia.
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PMID:Mitoxantrone: a novel anthracycline derivative. 304 48

Etoposide is a semi-synthetic, topoisomerase active podophyllotoxin derivative which frequently causes deletions and rearrangements on chromosomes 11q23 and 11q22. It can cause therapy-related, acute myeloblastic leukemia in patients receiving the drug in a schedule-dependent manner. Here we present a case with acute lymphoblastic leukemia who developed secondary acute myeloblastic leukemia 28 months after the beginning of therapy which contained etoposide on an every-other-week schedule.
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PMID:Secondary acute myeloblastic leukemia in a child with acute lymphoblastic leukemia treated with epipodophyllotoxins. 750 69

Drugs that interact with DNA topoisomerases I and II hold great promise for the treatment of cancer, however, like many other anti-cancer agents, they are a double-edged sword and may themselves cause mutation and cancer. In vitro studies show that clinically effective agents, such as etoposide, doxorubicin and others, stabilize a ternary complex where topoisomerase II is covalently linked to DNA. This complex represents an intermediate in the topoisomerase-II catalyzed DNA supercoil relaxation reaction. Camptothecin and its analogues stabilize a similar ternary complex, in vitro, consisting of topoisomerase I covalently linked to DNA at single-strand breaks. Short-term tests of genotoxicity confirm that topoisomerase-interactive agents are mutagenic and suggest common mechanisms by which they induce mutation and selectively kill tumor cells. These agents induce sister-chromatid exchange, chromosomal aberrations and mutations in specific mammalian genes. Their propensity to induce small colonies in the L5178/TK+/(-)-3.7.2C assay implies that topoisomerase-interactive agents induce large DNA rearrangements and deletions. These may result from topoisomerase-subunit exchange at drug-stabilized ternary complexes or from attempts by the cell to bypass the replication block caused by stabilized ternary complexes. Studies in bacterial mutation assays suggest that topoisomerase-interactive agents may also induce mutations, albeit at a lower rate, through simple DNA intercalation or via generation of oxygen free radicals. Second malignancies observed in patients previously treated with topoisomerase II interactive agents suggest these may be an important clinical consequence of their capacity to induce mutation. In particular, a unique form of acute myelogenous leukemia is observed at strikingly high frequencies after treatment with relatively high doses of the epipodophyllotoxins etoposide and teniposide. This form of AML has been reported after the uses of other classes of topoisomerase-interactive agents as well. Cancer induction is therefore a toxic consequence predicted by short-term tests of genotoxicity and should be weighed against the potential therapeutic benefits of topoisomerase-interactive agents.
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PMID:International Commission for Protection Against Environmental Mutagens and Carcinogens. Mutagenicity and carcinogenicity of topoisomerase-interactive agents. 751 27

The human tri-thorax gene (HRX) also called ALL-1 (Acute Lymphocytic Leukemia-1) as well as MLL (Myeloid-lymphoid or Mixed-lineage Leukemia) gene, is disrupted in the majority of leukemias with chromosomal abnormalities involving 11q23. The alteration of the gene is related to leukemogenesis of various types such as acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), and acute mixed lineage leukemia. The gene is also rearranged in cases of secondary AML developing after exposure to chemotherapeutic agents, especially topoisomerase II inhibitors. In at least one report, genomic analysis of this recombination site showed the breakpoint to be a topoisomerase II binding site and that exposure to the inhibitor could induce the rearrangement. If exposure induces the rearrangement of the gene, secondary ALL as well as secondary AML could occur after exposure to these agents, because the type of leukemias with rearranged HRX gene is not limited to AML. We present here such a case of secondary ALL with this gene rearrangement which occurred during adjuvant chemotherapy for breast cancer. Although less cases of secondary ALL are reported in comparison with those of secondary AML, such case reports have been accumulating. The incidence of this type of leukemia should be clarified in the future.
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PMID:HRX gene rearrangement in secondary acute lymphoblastic leukemia. 754 29

Development of myelodysplasia (MDS) with subsequent progression to acute myeloid leukemia (AML) is an example of the multistep process of malignant transformation in which each step often relates to genetic abnormalities that can be directly seen as chromosomal aberrations. Therapy-related MDS and AML (t-MDS and t-AML) may serve as an ideal model for a study of the genetic evolution of MDS and AML because chromosomal abnormalities are observed in most cases and because the disease is often diagnosed early due to a close patient follow-up. The cytogenetic characteristics at diagnosis were studied in 137 consecutive cases of t-MDS and t-AML, including 22 new cases, and correlated with the clinical characteristics and the course of the disease. Balanced translocations to chromosome bands 11q23 and 21q22 represent primary steps in pathways leading directly to overt t-AML. Specific chromosomal deletions or losses, on the other hand, represent primary or secondary events in alternative pathways leading to t-MDS with potential for subsequent transformation to overt t-AML. Loss of a whole chromosome 7 (-7) or deletion of its long arm (7q-) and deletion of the long arm of a chromosome 5 (5q-) were the most frequent primary abnormalities significantly related to t-MDS. Loss of a whole chromosome 5 (-5) was also a primary event, but surprisingly, was observed equally in t-MDS and in t-AML. Deletion of chromosome 13, including bands q13q14, was another less common primary aberration of t-MDS. Except for -7 and del(13q), these primary aberrations were most often observed together with secondary abnormalities. These included balanced aberrations involving band 3q26 and various deletions of chromosome 3, a gain of a whole chromosome 8, deletions of the short arm or loss of chromosomes 12 and 17, loss of a whole chromosome 18, and deletions of the short arm of chromosome 21. Deletions or loss or chromosomes 5 and 7 were significantly associated with previous therapy with alkylating agents (P = .002), and balanced translocations to chromosome bands 3q26, 11q23, and 21q22 were significantly associated with previous therapy with drugs targeting DNA-topoisomerase II (P < .00005). Other characteristic aberrations were not related to any specific type of therapy. The molecular changes believed to contribute to the development of t-MDS and t-AML have been identified for many of these chromosomal abnormalities.
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PMID:Different genetic pathways in leukemogenesis for patients presenting with therapy-related myelodysplasia and therapy-related acute myeloid leukemia. 757 62

We report a case of therapy-related acute myeloid leukemia (t-AML), M4 FAB subtype, with t(10;11)(p14;q21) chromosome abnormality developed in a patient treated for acute promyelocytic leukemia (APL) after 4 years of continuous complete remission (CCR). Two distinct forms of t-AML have been described: the classical type and the second type. Our case has many characteristics in common with the second type of t-AML such as: exposure to topoisomerase II active agents (idarubicin (IDA), mitoxantrone (MITOX), etoposide (VP16)), M4 FAB subtype, a latency period of 39 months and absence of a preleukemic phase. However, it differs in the chromosome 11 breakpoint (band q21 instead of q23) and absence of ALL-1 (Hrx, MLL, Htrx) gene involvement. This can represent the second observation of t-AML occurring after treatment for APL.
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PMID:Therapy-related acute myelomonocytic leukemia following successful treatment for acute promyelocytic leukemia. 765 28

Multidrug resistance (MDR) is associated with poor prognosis in leukemia, and anthracyclines, which are used in the treatment of leukemia, are associated with the expression of P-glycoprotein and the development of MDR. We report here that idarubicin, a new anthracycline approved for use in the treatment of acute myelogenous leukemia (AML), did not induce P-glycoprotein expression in the K562 human leukemia cell line under conditions where daunorubicin, doxorubicin and epirubicin did induce expression of P-glycoprotein. The P-glycoprotein expressing, multidrug resistant sublines developed to daunorubicin (K/DNR), doxorubicin (K/DOX) and epirubicin (K/EPR) were cross-resistant to the other anthracyclines and to vinblastine, taxol, colchicine and actinomycin D, but were not resistant to idarubicin or etoposide. The idarubicin treated subline, K/IDA, was only resistant to taxol but was 12-fold sensitized to etoposide, suggesting that idarubicin had affected topoisomerase II in this subline.
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PMID:Development of drug resistance is reduced with idarubicin relative to other anthracyclines. 767 Jan 42

We examined clinical, morphologic, and cytogenetic features and ALL-1 (MLL, Htrxl, HRX) gene rearrangements in 17 cases of secondary leukemia that occurred 11 months to 9 years from diagnoses of primary cancers in children who received topoisomerase II inhibitors or developed secondary leukemias typical of those associated with this therapy. Primary diagnoses included nine solid tumors and eight leukemias. Ten secondary leukemias were acute myeloid leukemia (AML), one was of mixed lineage, two were acute lymphoblastic leukemia (ALL), and four presented as myelodysplasia. Of 15 cases with 11q23 involvement, 11 (73%) were cytogenetically identifiable; four cases had molecular rearrangement only. By Southern blot, rearrangements within the ALL-1 gene were similar to sporadic cases. The results of this analysis suggest the following: (1) In most pediatric cases of topoisomerase II inhibitor-associated leukemia, there is disruption of the breakpoint cluster region of the ALL-1 gene at chromosomal band 11q23. (2) Exposure histories vary in secondary 11q23 leukemia, as the only topoisomerase II inhibitor was dactinomycin in one case, and, in another case, no topoisomerase II inhibitor was administered. (3) There is clinical, morphologic, cytogenetic, and molecular heterogeneity in pediatric secondary 11q23 leukemia. (4) There are some survivors of pediatric secondary 11q23 leukemia, but the outcome is most often fatal.
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PMID:ALL-1 gene rearrangements in DNA topoisomerase II inhibitor-related leukemia in children. 775 57

Leukemias with abnormalities in chromosome 11q23 occur frequently after exposure to topoisomerase II-reactive drugs. We investigated the characteristics and outcome of patients with de novo or secondary acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS) with abnormalities in chromosome 11q. Sixty-one patients had 11q abnormalities. Alterations involved 11q23 in 38 patients and other 11q abnormalities in 23. Sixteen patients had secondary disease, 12 involving 11q23, and four with other 11q abnormalities; 26 patients with de novo disease had 11q23 abnormalities and 19 other 11q abnormalities. The most common 11q23 abnormality was t(9;11), significantly more common in secondary (9/12) than in de novo (6/26) leukemias (p = 0.003). There were no significant differences in clinical characteristics between de novo and secondary groups involving 11q23. Five of 12 patients (42%) with secondary and 20/26 (77%) with de novo disease achieved complete remission (p = 0.05). Median survival was 6 weeks in the secondary group and 71 weeks in the de novo group (p = 0.001). There were no long-term survivors in either group. Results are similar when other 11q abnormalities are included. Adults with AML or MDS with 11q abnormalities secondary to prior chemotherapy have a worse prognosis than patients presenting de novo. However, 11q abnormalities define a population with a poor prognosis even when presenting de novo.
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PMID:Abnormalities in the long arm of chromosome 11 (11q) in patients with de novo and secondary acute myelogenous leukemias and myelodysplastic syndromes. 780 7


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