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

A fluorescence image cytometry technique was developed to measure the effects of topotecan, a topoisomerase I inhibitor, on the nuclear expression of topoisomerase II alpha in a series of patients with refractory or relapsed acute myeloid leukemia (AML). We used a commercially available affinity-purified rabbit polyclonal antibody and a fluorescein-conjugated secondary antibody. By using DAPI as a DNA counterstain and dual wavelength excitation, it was possible to measure enzyme expression in the cell nucleus, and to examine its cell cycle phase distribution. In human acute leukemia cell lines, topoisomerase II alpha expression was greatest in late S and G2 phases, but in leukemia patient samples the enzyme expression appeared to be much less cell cycle dependent. There was considerable interpatient variation in the effects of topotecan on topoisomerase II alpha expression in the leukemia patients, with a threefold increase in the median value after 48 h followed by a decline to pretreatment levels after 5 days of treatment with the topoisomerase I inhibitor. Although these findings should be treated with caution because of the small number of cases studied, they support the prediction that topoisomerase I inhibitors might be capable of increasing sensitivity to topoisomerase II active drugs such as anthracyclines and epipodophyllotoxins by upregulating topoisomerase II expression. They also illustrate the potential value of fluorescence image cytometry for making sequential measurements of the effects of drug resistance modulating agents in cancer patients.
...
PMID:Effects of topoisomerase I inhibition on the expression of topoisomerase II alpha measured with fluorescence image cytometry. 891 17

During the last decade the frequency of therapy-related acute leukemia (t-leuk) and myelodysplastic syndrome (t-MDS) has been increasingly observed. Over the past 15 years, we treated 56 patients with t-leuk who had received prior chemotherapy (39%), radiotherapy (11%), or both (45%). The drugs received included alkylating agents and topoisomerase II inhibitors. The primary tumors included hematological malignancies (49%) and solid tumors such as breast or ovarian cancer. The median age at diagnosis of the primary tumor was relatively young (43 years +/- 18). Twelve patients had more than one primary tumor and 31 patients had a family history of malignancy. Karyotypic abnormalities were found in 91% of the patients. Prognosis was uniformly poor, with an overall median survival of 10 months. Twelve of the 18 patients examined (67%) had a multidrug resistance phenotype. P53 genes of the leukemic cells, as well as the original tumors, were analyzed in 21 patients using polymerase chain reaction (PCR) with single-stranded conformation polymorphism analysis followed by sequencing. P53 mutations were identified in 38% of these patients, a relatively high prevalence compared with other forms of MDS or de novo acute myeloid leukemia. Mutations were nongermline and restricted to the leukemic cells. We identified different p53 mutations in the various primary tumors of individual patients. The presence of a mutator phenotype was assessed by PCR analysis of microsatellites in eight loci (one trinucleotide repeat sequence, four dinucleotide, and three mononuclear repeat sequences). Microsatellite instability in two to seven loci were found in 15 of 16 (94%) of the patients. This instability is compatible with a mutator phenotype, which predisposes the patients to the development of malignancies including t-leuk.
...
PMID:Microsatellite instability and p53 mutations in therapy-related leukemia suggest mutator phenotype. 894 66

We report on 2 patients with acute leukemia who had an 11q23 chromosomal aberration as an additional change after treatment with etoposide and mitoxantrone, agents that affect topoisomerase II (Topo II). One patient with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (L2) received chemotherapy, including 1,000 mg of etoposide and 75 mg of mitoxantrone. She relapsed 10 months later. Analysis at time of relapse showed a chromosomal aberration of del(11)(q23) as an additional cytogenetic change. The other patient was diagnosed with acute monoblastic leukemia (M5a) and received two autologous peripheral blood stem-cell transplantations. Her cumulative doses of etoposide and mitoxantrone were 6,000 mg and 42 mg, respectively. She also relapsed, and analysis at that time revealed del(11)(q23) as an additional chromosomal aberration. The mixed lineage leukemia/myeloid-lymphoid leukemia (MLL) gene was not rearranged in either case, making these cases distinct from previously described therapy-related leukemias caused by Topo II inhibitors. Based on these two cases, it may be that Topo II inhibitors can cause clonal evolution affecting chromosome band 11q23.
...
PMID:11q23 aberration is an additional chromosomal change in de novo acute leukemia after treatment with etoposide and mitoxantrone. 894 68

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.
...
PMID:Mutation frequency and spectrum in lymphocytes of small cell lung cancer patients receiving etoposide chemotherapy. 933 Nov 3

A woman with t(15;17) and PML/RAR alpha positive acute promyelocytic leukemia (APL-M3v) achieved a complete remission (CR) with cytogenetic and molecular conversion, after one-month ATRA plus idarubicin treatment. During CR, less than one-month after consolidation therapy with topoisomerase II inhibitors, a novel t(11;19) (q13;q13.3) was detected in peripheral blood stem cells and later in harvest bone marrow cells. Persisting CR and the negativity for BCL1 and PRAD1 genes rearrangement, the autotransplantation was performed, with good outcome. The patient is still in CR eighteen months post-transplant, in spite of the persistence of a small t(11;19) clone in BM cells. The emergence of a novel chromosomal change during CR of acute leukemia is a rare phenomenon. This is the first t(11;19)(q13;q13.3) described in APL. This finding raises the issue of whether the abnormal karyotypes at remission might represent a risk of tumor recurrence. The meaning of this genomic instability is yet unknown.
...
PMID:Occurrence of a novel t(11;19)(q13;q13.3) in complete remission of acute promyelocytic leukemia. 946 Apr 97

The activity of topotecan was evaluated in patients with myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML). Sixty patients with a diagnosis of MDS (n = 30) or CMML (n = 30) were treated. Their median age was 66 years, with 50 patients (83%) being over 60 years of age at time of study entry. Chromosomal abnormalities were present in 50% of patients and thrombocytopenia of less than 50 x 10(9)/L in 50%. Topotecan was administered as 2 mg/m2 by continuous infusion over 24 hours daily for five days (10 mg/m2 per course) every 4 to 6 weeks for two courses, then at maximum tolerated dose level (1-2 mg/m2 by continuous infusion over 24 hours daily for five days) once every 4-8 weeks for a maximum of 12 courses. Evaluation of outcome and of differences among subgroups was performed according to standard methods; the criteria for response were those used for acute leukemia. Nineteen patients (31%) achieved a complete response (CR). A CR was achieved in 11 of 30 patients with MDS (37%) and in eight of 30 with CMML (27%). A CR was achieved in 10 of 23 patients with previously untreated MDS (43%). Eight of 11 patients who presented with cytogenetic abnormalities (five of which involved chromosome 5 and/or 7 abnormalities) and achieved CR, were evaluated cytogenetically in CR: all were cytogenetically normal in CR. Characteristics associated with a higher CR rate were lack of previous chemotherapy, absence of ras oncogene mutations, and presence of less than 10% monocytes in either peripheral blood or bone marrow. In contrast, CR rates were similar by different agent groups, by different karyotype abnormalities, and by other pre-therapy peripheral blood counts. Non-myelosuppressive side effects were mucositis in 67% of patients (severe [grade 3-4] 23%), diarrhea in 38% (severe 17%), and nausea and vomiting in 28% (severe 5%). Febrile episodes during neutropenia occurred in 85% of patients and documented infections in 47 %. Mortality in the first four weeks was 20%. With a median follow-up duration of 31 months, the 12 month survival rate was 38%, median survival time 10.5 months, and median remission duration 7.5 months. In summary, topotecan has significant single-agent activity in MDS and CMML. Complete responses associated with topotecan therapy often involve the disappearance of abnormal, poor-prognosis karyotypes, which is particularly encouraging. Future strategies to optimize topotecan's role include combination regimens with topoisomerase II reactive agents, cytarabine, or hypomethylating agents (azacytidine and decitabine).
...
PMID:Results of topotecan single-agent therapy in patients with myelodysplastic syndromes and chronic myelomonocytic leukemia. 992 42

The oral antitumor drugs against hematological malignancies are summarized. Sobuzoxane, a topoisomerase II inhibitor, is useful for the treatment of lymphoma, especially adult T cell leukemia/lymphoma. Sobuzoxane has an effect to protect against doxorubicin cardiotoxicity. Cytarabine ocfosfate, a derivative of cytosine arabinoside, is a useful agent against acute leukemia and MDS, especially RAEB, RAEB in T, CMMoL. The JALSG AML 92 study for APL with all-trans retinoic acid resulted in a 89% CR rate in 196 and 64% 4-year DFS in CR cases. Hydroxycarbamide is can control the WBC in CML. This agent is also effective for other myeloproliferative disorders, such as acute leukemia and MDS. Oral administration of 50 mg etoposide daily showed a good outcome in old patients with malignant lymphoma. For old patients and those with refractory hematological malignancies, oral administration of these agents can offer a new form of palliative therapy to allow them to remain at home while maintaining a high quality of life.
...
PMID:[Oral antitumor drugs for hematological malignancies]. 1006 91

Recent molecular-genetic studies have revealed that in the majority of patients with secondary leukemia induced by topoisomerase II (topo II) inhibitors and also with infantile acute leukemia (IAL), the breakpoints are clustered within scaffold attachment regions (SARs) of 3'-MLL-bcr near exon 9. Genistein, abundant in soybeans, is reported to be a potent nonintercalative topo II inhibitor. It interferes with the break-reseal reaction of topo II by stabilizing a cleavable complex, which in the presence of detergents, results in DNA strand breaks. The present study revealed that genistein induced chromatid-type aberrations, in which chromatid exchanges are often observed. Genistein seems to act in a manner very similar to that of VP-16, although the latter is reported to produce both chromatid- and chromosome-type aberrations. In view of this pharmacological similarity between genistein and VP-16, and also the similarity of breakpoint clustering regions within the MLL gene in reported cases with secondary leukemia and IAL, genistein may be largely responsible for the development of IAL.
...
PMID:Infantile leukemia and soybeans--a hypothesis. 1072 Jan 57

Prolonged exposure to a topoisomerase I inhibitor may increase expression of topoisomerase II, making cells more susceptible inhibitors of that enzyme. This study was undertaken to establish the maximum tolerated dose (MTD) of a topotecan/topoisomerase II inhibitor sequential combination that may be active in acute leukemia, and to evaluate the effects of in vivo exposure to topotecan on topoisomerase II levels in leukemic blast cells as measured by image cytometry. Patients who were eligible for this phase I study had relapsed or refractory acute myeloid leukemia (< or = 2 prior regimens) or CML blast crisis (0 or 1 prior regimen). Topotecan was given as a 5 day continuous i.v. infusion and was to be escalated through three levels (1.5, 1.75 and 2.0 mg/m2 day), followed by etoposide at two dose levels (100 and 150 mg/m2) i.v. bolus days 6, 7 and 8. Topoisomerase IIalpha levels in leukemic blasts from bone marrow were measured by image cytometry prior to starting treatment, on day 5 of topotecan infusion and on day 28; and daily during topotecan in peripheral blood blasts. Dose-limiting toxicity was seen in two of six patients at the first dose level (topotecan 1.5 mg/m2/day, etoposide 100 mg/m2/day; > or = grade 3 mucositis in both cases). This cohort was expanded to 10 patients; no further non-hematologic dose-limiting toxicity was observed, but given the extent of toxicity seen, further dose escalation was judged not to be feasible. Topo IIalpha levels increased in peripheral blood blasts during the first 72 h of topotecan infusion and returned to near baseline by day 5, whereas levels appeared to decrease in bone marrow blasts by day 5 compared to pretreatment. One complete hematologic and cytogenetic remission in a patient with CML blast crisis was observed in the 10 patients evaluable for response. The sequential administration of topotecan 1.5 mg/m2/day continuous infusion for 5 days followed by etoposide 100 mg/m2/day x 3 is the recommended phase II dose for this schedule. Topotecan increases topo IIalpha expression in vivo in leukemia cells, but levels of the enzyme are cell cycle dependent. Pharmacodynamic evaluation of the sequential or combination administration of novel antileukemic agents may help improve treatment strategies in acute leukemia.
...
PMID:Phase I trial of sequential topotecan followed by etoposide in adults with myeloid leukemia: a National Cancer Institute of Canada Clinical Trials Group Study. 1008 24

The t(3;21)(q26;q22) is a recurring chromosomal abnormality in blastic crisis of chronic myelogenous leukemia (CML) and in therapy-related myelodysplastic syndrome and acute leukemia. In order to clarify the genetic recombination mechanism underlying the t(3;21), we molecularly cloned the breakpoints and determined their nucleotide sequence in a case of CML in blastic crisis with t(3;21). Near the breakpoint on chromosome 21, three homopyrimidine (CT)-rich sequences were found. We also identified a sequence homologous to the topoisomerase II binding and cleavage consensus sequence surrounding the breakpoint on chromosome 3, and two topoisomerase II binding and cleavage consensus sequences near the breakpoint on chromosome 21. In addition, around the breakpoint on chromosome 21, four chi-like sequences, potential consensus signals for activating recombination, were found. There were no Alu sequences or antigen receptor gene-like heptamer/nonamer signal sequences within the breakpoints on chromosomes 3 and 21. The breakpoints were found adjacent to the topoisomerase II binding and cleavage consensus sequence or the homopyrimidine-rich sequence. Furthermore, the chi-like sequences and the homopyrimidine-rich sequence were detected on chromosome 21 but not on chromosome 3. Genes Chromosomes Cancer 26:92-96, 1999.
...
PMID:Molecular characterization of the genomic breakpoints in a case of t(3;21)(q26;q22). 1044 Oct 11


<< Previous 1 2 3 4 5 6 Next >>

---