Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:5.99.1.2 (topoisomerase)
 9,166 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aim of this study was to evaluate the activity of topotecan in patients with myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML). Forty-seven patients with a diagnosis of MDS (n = 22) or CMML (n = 25) were treated. The median age was 66 years. Chromosomal abnormalities were present in 70% and thrombocytopenia less than 50 x 10(3)/microL in 51%. Evaluation of outcome and of differences among subgroups was performed according to standard methods; the criteria for response were those used for acute leukemia. Topotecan was administered as 2 mg/ m2 by continuous infusion over 24 hours daily for 5 days (10 mg/m2 per course) every 3 to 4 weeks until remission, then once every month for a maximum of 12 courses. Thirteen patients (28%) achieved a complete response (CR) and six (13%) had hematologic improvement. A CR was achieved in six of 22 patients with MDS (27%) and in seven of 25 with CMML (28%). All eight patients who presented with cytogenetic abnormalities (five chromosome 5 or 7 abnormalities) who achieved CR were cytogenetically normal in CR. Characteristics for which there was evidence of association with a higher response rate were lack of prior chemotherapy, less than 10% marrow monocytes, and absence of RAS oncogene mutations. In contrast, CR rates were similar in patients with or without abnormal karyotypes. Mucositis occurred in 64% of patients (severe in 19%) and diarrhea in 32% (severe in 13%). Febrile episodes occurred in 85% of patients and documented infections in 47%. With a median follow-up duration of 8 months, the 12-month survival rate was 38%, median survival time 10.5 months, and median remission duration 7.5 months. We conclude that topotecan has significant activity in MDS and CMML, with acceptable side effects. Future studies will investigate topotecan combined with topoisomerase II reactive agents, cytarabine, or hypomethylating agents (azacytidine and decitabine).
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PMID:Topotecan, a topoisomerase I inhibitor, is active in the treatment of myelodysplastic syndrome and chronic myelomonocytic leukemia. 883 38

CBP, which is located on 16p13 and encodes a transcriptional adaptor/coactivator protein, has been shown to fuse by the t(8;16)(p11;p13) translocation to MOZ on 8p11 in acute myeloid leukemia. We found a t(11;16)(q23;p13) in a child with therapy-related chronic myelomonocytic leukemia. Subsequent reverse transcriptase-polymerase chain reaction and direct sequencing analyses revealed the MLL-CBP fusion transcript in CMML cells. Because 11q23 translocations involving MLL and t(8;16) involving MOZ and CBP have been reported in therapy-related leukemias, both the MLL and CBP genes may be targets for topoisomerase II inhibitors. Accordingly, we believe that most t(11;16)-associated leukemias may develop in patients who have been treated with cytotoxic chemotherapy for primary malignant diseases.
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PMID:Novel MLL-CBP fusion transcript in therapy-related chronic myelomonocytic leukemia with a t(11;16)(q23;p13) chromosome translocation. 929 Sep 55

Myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) are heterogeneous disorders for which there exist few active therapies and where the standard of care is still considered supportive. Identification of new effective therapies in MDS and CMML is a high priority for hematologic oncologists. We have evaluated the efficacy of single-agent topotecan, a topoisomerase I inhibitor, in patients with MDS (refractory anemia with excess blasts [RAEB] and refractory anemia with excess blasts in transformation [RAEB-T]) and CMML. Sixty patients (MDS = 30; CMML = 30) with a median age of 66 years were treated. Chromosomal abnormalities were present in half of the patients, as was thrombocytopenia. Topotecan was administered at 2 mg/m2 by continuous intravenous infusion over 24 hours daily for 5 days every 4 to 6 weeks until remission, followed by one course every 4 to 8 weeks for a maximum of 10 courses. Nineteen patients (32%) achieved a complete response (CR); seven had hematologic improvement. CRs were observed in 11 of 30 patients with MDS (37%) and eight of 30 patients with CMML (27%). Conversion to diploid karyotype was observed in eight patients with karyotypic abnormalities at diagnosis who later achieved a CR. History of prior chemotherapy and monocytosis was associated with poor prognosis. Mutation of the RAS oncogene was found in six CMML patients (20%), and none responded to topotecan therapy. The estimated 12-month survival rate was 33%, the median survival time was 9.3 months, and the median remission duration was 7 months. The most significant toxicities were gastrointestinal, including mucositis (67%; severe 23%) and diarrhea (38%; severe 17%). Febrile episodes were noted in 85% of the patients, while documented infection occurred in 47%. Topotecan has demonstrated significant single-agent activity in MDS and CMML with generally manageable side effects. Future studies will evaluate topotecan-based combination therapies with topoisomerase II reactive agents, cytarabine, alkylating agents, and hypomethylating agents.
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PMID:Topotecan in the treatment of hematologic malignancies. 977 79

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).
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PMID:Results of topotecan single-agent therapy in patients with myelodysplastic syndromes and chronic myelomonocytic leukemia. 992 42

Topotecan, a topoisomerase-I inhibitor is an active drug in the treatment of AML and MDS. To evaluate its toxicity and efficacy in a combination regimen with cytarabine, we conducted a clinical phase I/II trial in patients with relapsed acute myeloid leukemia (AML) or relapsed or newly diagnosed MDS RAEB, RAEB-t or CMML. Twenty-one patients (11 AML, 10 MDS/CMML) entered the study and were treated with 1.25 mg/m2 topotecan as continuous intravenous infusion daily for 5 days and cytarabine 1.0 g/m2 by infusion over 2 h daily for 5 days (TA). Cycles were repeated on day 28. The median observation time was 131 weeks (range: 36-196 weeks). A total of 37 cycles of TA were administered. In 1 patient, the dose of TA had to be reduced and in 1 patient, there was a treatment delay for the second cycle, both because of hematologic toxicity. The most frequent non-hematologic side-effect of TA was fever, which occurred in 17 patients (89%) with temperatures over 38 degrees C. None of the patients died due to any treatment-related toxicities, but 2 patients (10%) died within 1 month due to disease progression. A CR was achieved in 7 patients (33%), 3 of whom were MDS and 4 AML. A partial remission was reported in 8 patients (38%), no change of disease in 2 patients (10%) and progressive disease in 4 patients (19%). The median remission duration was 18 weeks (range 2-161 weeks) for MDS patients and 11 weeks (range 2-49 weeks) for AML patients. The time to progression for patients of 60 years and older (n = 10) was 16 weeks (range 2-49 weeks) and the survival was 32 weeks (range 2-119 weeks). TA is a feasible and efficacious chemotherapeutic combination for the treatment of MDS RAEB, RAEB-t, CMML and AML. For patients of 60 years and older, this regimen is also a safe option.
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PMID:Phase I/II clinical study of topotecan and cytarabine in patients with myelodysplastic syndrome, chronic myelomonocytic leukemia and acute myeloid leukemia. 1516 Sep 42

Chronic myelomonocytic leukaemia (CMML) is a preleukaemic condition with myeloproliferative features, and classified as a part of myelodysplastic syndrome (MDS). Other than alkylating agents and topoisomerase II inhibitors, there is less evidence that chemotherapeutic drugs are associated with therapy-related CMML, acute leukaemia or MDS. We present a patient who developed CMML within 2 years of platinum-based chemotherapy for a metastatic non-small cell lung cancer. He received a cumulative dose of 240 mg/m(2) of cisplatin, and 1123 mg/m(2) of carboplatin before developing CMML. The cytogenetic study revealed trisomy 8. This is the first reported case that links platinum-based therapy with development of CMML with trisomy 8. Although the relationship between platinum therapy and the development of CMML is difficult to assess due to combinational nature of therapy in most cases, physicians should consider the possibility of CMML in patients with symptoms or signs suggestive of haematologic malignancy after platinum therapy.
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PMID:Chronic myelomonocytic leukaemia after platinum-based therapy for non-small cell lung cancer: case report and review of the literature. 1688 13

Current APL chemotherapy protocols usually include high-dose anthracyclines, mitoxantrone, and epipodophillotoxins, which are topoisomerase II inhibitors of high leukemogenic potential. In the last years, several case reports of myelodysplastic syndrome (MDS) or AML (different from APL), occurring during the course of APL have been made. We report herein a first case of CMML with monosomy 7 occurring after treatment of APL.
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PMID:Secondary chronic myelomonocytic leukemia with monosomy 7 after successful treatment of acute promyelocytic leukemia. 1817 33