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

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Query: EC:5.99.1.2 (topoisomerase)
9,166 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

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

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

The National Cancer Institute (NCI) recently alerted clinicians to the possibility that patients, entered on a NCI-sponsored cooperative group trial of doxorubicin and cyclophosphamide adjuvant therapy for breast cancer, may be at high risk of developing secondary acute myeloid leukemia (AML). Secondary AML following standard doses of doxorubicin and cyclophosphamide is uncommon, suggesting that the high risk on this trial may result from its higher-than-standard doses of chemotherapy. However, the cases of secondary AML were characteristic of the type that follows treatment with topoisomerase II-active agents, especially etoposide, and this type of secondary AML is rare after treatment with either cyclophosphamide or doxorubicin at any dose. We raise the possibility that another component of this trial, hematopoietic growth factors to decrease the toxicities related to myelosuppression, may play an important role in the development of secondary AML. Growth factors not only stimulate hematopoietic progenitor proliferation and differentiation, they also regulate hematopoietic cell survival by interfering with apoptosis (programmed cell death). Inhibition of apoptosis by a variety of genetic factors is an important mechanism of oncogenesis, and appears to be the initiating event in some malignancies. Growth factor-mediated suppression of the apoptotic death of hematopoietic progenitors damaged by chemotherapy may contribute to their leukemic transformation.
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PMID:Are growth factors leukemogenic? 855 25

Three patients with secondary acute leukaemia after treatment with topoisomerase II inhibitor agents are described. Two patients had acute myeloid leukaemia (AML). FAB M5a, one had pro-B-acute lymphoblastic leukaemia (ALL). The interval between initiation of chemotherapy and the onset of secondary acute leukaemia was 19-20 months. 11q23 rearrangements were detected in all cases. They were due to translocations t(11;19) (q23;p13.3), t(11;16)(q23;p13) and t(4;11)(q21;q23), respectively. Fluorescence in situ hybridization (FISH) with Yeast Artificial Chromosome (YAC) probe 13HH4 spanning the ALL-1 gene on 11q23 confirmed that in each case the ALL-1 gene had been disrupted by the translocations. The study underlined the relationship between the development of secondary acute leukaemias with 11q23 rearrangement and previous chemotherapy with topisomerase II inhibitor agents. So far, however, only six adult patients with secondary ALL with t(4;11) after treatment with topoisomerase II inhibitor agents have been reported. All with t(4;11) mostly occurs in infants or young children. Our patient received epirubicin continuously for >19 months. This indicates that both myeloid and lymphoid leukaemias with involvement of the ALL-1 gene can be induced by exogenous agents, especially topoisomerase II inhibitors. Thus they may have a common biological background. This hypothesis was substantiated by means of combined immunophenotyping and FISH (FICTION). In the case of AML M5a with t(11;19), the tumour cells with ALL-1 rearrangement expressed CD34. Moreover, the pro-B-ALL with t(4;11) was CD34 positive. These findings suggest that the cell of origin of secondary AML and ALL with 11q23 rearrangement is an immature haemopoietic progenitor cell.
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PMID:Secondary acute leukaemias with 11q23 rearrangement: clinical, cytogenetic, FISH and FICTION studies. 861 34

Now that a substantial group of cancer patients has such a favourable prognosis, it has become increasingly important to evaluate the long-term complications of treatment. Of all late effects of treatment, secondary leukaemia is one of the most serious. Increased risk of AML has been observed both after RT and after CT; however, several types of CT have much stronger leukaemogenic properties than RT. Limited field radiation in the therapeutic dose range is associated with very little or no increased risk of leukaemia, which has been attributed to cell killing at the higher radiation doses. With respect to CT, two different syndromes of treatment-related AML have been recognized. Risk of alkylating agent-related AML is highest in the 5-10 year follow-up period and seems to decrease afterwards. This type of leukaemia is often preceded by MDS, and is characterized by deletions of chromosomes 5 and 7. Leukaemias related to treatment with the topoisomerase II inhibitors are characterized by a short induction period, presentation as myelomonocytic or monocytic leukaemia (rather than MDS) and balanced chromosomal translocations involving bands 11q23 and 21q22. This review addresses the risk of secondary AML and MDS following treatment of HD, NHL, testicular cancer, ovarian cancer, breast cancer and paediatric malignancies. In patients with HD, the risk of AML is higher with an increasing number of mechlorethamine-procarbazine-containing cycles, a greater number of CT episodes, and after splenectomy. The majority of data shows that RT does not add to the leukaemia risk from CT, but this issue is still surrounded by some controversy. ABV(D)-treated patients have a very low risk of AML. Generally, patients with NHL, testicular cancer and breast cancer experience much lower risk of AML than patients with HD. NHL and breast cancer treatment regimens with cumulative cyclophosphamide doses of 20 g or less do not confer an appreciable increase of AML. Recently, strongly increased AML risk has been observed following autologous bone marrow transplantation and other dose intensification strategies. Risk factors for this excess remain to be defined. PVB treatment for testicular cancer is not followed by increased leukaemia risk, but modern etoposide-containing regimens do confer excess risk, of which the magnitude at conventional drug doses is not yet well known. High risk of leukaemia has been reported in children treated with epipodophyllotoxins. The leukaemogenic hazards of cancer treatment should be weighed against their therapeutic benefits.
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PMID:Risk of acute myelogenous leukaemia and myelodysplasia following cancer treatment. 873 May 51

Etoposide, a topoisomerase II inhibitor, is a chemotherapeutic agent that is used in the treatment of a wide variety of neoplasms, including small cell lung cancer, germ cell cancer, testicular cancer, acute leukemia, and lymphoma. Although it has proven valuable, etoposide is also a known mutagen and has been implicated as a causative agent of treatment-related secondary acute nonlymphocytic leukemia. We have investigated the induction of mutation following etoposide treatment in vivo using the hypoxanthine phosphoribosyltransferase (hprt) T-cell cloning assay in small cell lung cancer patients receiving single-drug etoposide chemotherapy. This report presents results on the monitoring of 12 patients (mean age, 74.8 +/- 6.0 years; range, 66-83 years) before, during, and after chemotherapy. The treatment regimen included up to six cycles of oral etoposide given in twice-daily 50-mg tablets for 10-14 days, separated by 2 weeks of rest. Peripheral blood samples were collected on the first day of each cycle prior to treatment. Patients received one to six etoposide cycles and were followed for 0.7-5.3 months after the start of chemotherapy (total etoposide dose, 1.4-8.4 g). Results from the pooled data show no significant increase in the hprt mutant frequency (pretreatment, 46 x 10(-6) +/- 38 x 10(-6), versus posttreatment, 55 x 10(-6) +/- 46 x 10(-6)), although considerable interpatient variability was observed. Of a total of 424 selected mutants, 228 were analyzed by sequencing hprt cDNA. Spectra of 56 pretreatment and 147 posttreatment mutations revealed significant enhancement of AT-->TA transversions and a concomitant decrease in the number of GC-->TA transversions in posttreatment spectra, when they were compared with pretreatment or control spectra. No evidence for the induction of gross deletions or rearrangements was found in the spectra of mutants that were recovered from patients after etoposide treatment. The lack of enhanced mutant frequency after treatment suggests that the etoposide chemotherapy was not particularly effective in inducing mutation, as measured by the hprt assay. It is proposed that mutated cells are eliminated through apoptosis due to accumulated DNA damage.
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PMID:Mutation frequency and spectrum in lymphocytes of small cell lung cancer patients receiving etoposide chemotherapy. 933 Nov 3

The inhibition of topoisomerase II (topo II) is a very powerful principle of chemotherapy and topo II inhibiting drugs are the backbone of most chemotherapeutic strategies. However, secondary malignomas can occur after treatment. Typically, secondary acute myeloid leukemia (t-AML) after treatment with topo II inhibitors has a shorter latency period than t-AML following alkylator therapy. Fragments originating from chromosome breakage as well as whole chromosomes which are not correctly distributed during mitosis give rise to micronuclei in the next interphase. Micronucleus formation has become an important endpoint in genotoxicity testing. In an effort to test the suitability of the micronucleus assay for predictive purposes, we have analyzed three human tumor cell lines for cell growth as well as micronucleus induction after treatment with four clinically used topo II inhibitors. Micronuclei were induced at levels of low toxicity by etoposide, mitoxantrone, daunorubicin and idarubicin. The induction of micronuclei was a more sensitive indicator of drug effects than reduction in cell growth. Thus, micronucleus induction may assist in the prediction of the potency of a chemotherapeutic agent for induction of secondary malignomas.
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PMID:Are topoisomerase II inhibitor-induced micronuclei in vitro a predictive marker for the compounds' ability to cause secondary leukemias after treatment? 1004 55

The ATP assay is a short term in vitro chemosensitivity assay where the amount of viable cells are determined by their content of ATP. The aim of the study was to compare the in vitro results of six cytostatic drugs to the clinical outcome in 83 acute non-lymphocytic leukemia (ANLL) patients. The secondary ANLL at diagnosis showed an in vitro resistance to daunorubicin that was significantly higher compared to de novo ANLL at diagnosis (P<0.003). De novo ANLL at diagnosis that achieved complete remission (CR) were significantly more sensitive to daunorubicin compared to those who didn't achieve CR (P<0.05). There was an vitro correlation between topoisomerase II active drugs but not between these drugs and ara-C. In vitro ara-C sensitivity (< or = the median of the de novo ANLL at diagnosis) was correlated to poor overall survival (P = 0.02). In vitro sensitivity to daunorubicin and mitoxantrone was associated with prolonged disease free survival (P = 0.03 and P = 0.04). We conclude that despite significant correlation to clinical parameters for daunorubicin and mitoxantrone the predictive value of the ATP assay in this material was insufficient for directing therapy.
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PMID:In vitro chemosensitivity testing in acute non lymphocytic leukemia using the bioluminescence ATP assay. 1078 67


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