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)

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

Standard antileukemic chemotherapy induces complete remission in approximately half of patients with high-risk (HR) myelodysplastic syndrome (MDS). Intensification of induction therapy by the use of intermediate- or high-dose cytosine arabinoside in combination with fludarabine, idarubicin, or topotecan seemingly improved complete response (CR) rates, particularly in patients with poor prognosis karyotypes. The various high-intensity regimens appear to be comparable in inducing CR, although some are better tolerated with low mortality even in advanced-age populations with MDS. The encouraging early results with new agents, eg, topoisomerase inhibitors (topotecan) and hypomethylating agents (5-azacytidine), have been disappointing because long-term follow-up has shown continuous relapses. Regardless of the intensity of chemotherapy, remissions are short, even with continuation of intensive postremission therapy. Long-term disease-free survival remains dismal. In a large population with HR MDS treated with high-dose chemotherapy, only 5% of patients were alive at 3 years, and a majority of survivors were the younger patients with diploid karyotype refractory anemia with excess blasts in transformation. Further intensification of either induction chemotherapy or postremission therapy is unlikely to improve results with current drug combinations. With these results at hand, the role of intensive chemotherapy in the management of MDS remains controversial. Because CR status is associated with clinical benefits and possibly better survival, induction of CR should remain an important aim for HR MDS. The intensive combination chemotherapy may be integrated as an initial part of the management of HR MDS, as an alternative for patients not eligible for allogeneic bone marrow transplantation (BMT). Regimens with low early mortality, eg, topotecan plus intermediate dose Ara-C, could also be used to reduce tumor load prior to allogeneic BMT. Induction of CR should be attempted with the most effective and best tolerated regimens, particularly, but not only, in younger patients with good performance status regardless of karyotype. Postremission therapy remains a major challenge. It should involve either allogeneic BMT or investigational approaches to eliminate or control the minimal residual disease with different mechanisms In elderly patients, allogeneic "minitransplant" is an investigational alternative seeking to exploit graft-versus-tumor reaction. New agents, such as farnesyl transferase inhibitors (ras inhibitors), drug-antibody conjugates (Myelotarg), thalidomide, arsenic trioxide, maintenance chemotherapy with hypomethylating agents, or oral topoisomerase inhibitors along with agents modulating factors affecting growth and differentiation, should be explored to maintain remission with minimal compromise of quality of life. Although prognostic scoring systems such as the new International Prognostic Scoring System (IPSS) do not predict for initial response, IPSS continues to predict survival in patients treated with high-dose chemotherapy. Although activity of new agents could be rapidly assessed in single-arm pilot studies, the final merit of high-dose chemotherapy could be assessed only in well-designed randomized trials with patients assigned according to risk-based classification and evaluated for response by generally accepted and standardized criteria.
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PMID:Intensive chemotherapy for patients with high-risk myelodysplastic syndrome. 1103 61