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)

Before embarking on experimental therapies for progressive multifocal leukoencephalopathy (PML), the diagnosis needs to be unequivocally established. Improving the underlying immunodeficiency state is the best initial approach to the management of PML. Immunosuppressive therapies should be discontinued when feasible. In the patient with AIDS, highly active antiretroviral therapy should be administered; this appears to prolong survival. At present, no therapy has been demonstrated to be effective in a well-designed prospective trial. Cytosine arabinoside, which has demonstrated efficacy in vitro against JC virus, has not been effective when administered intravenously or intrathecally to patients with AIDS and PML. The failure of regimens employing cytosine arabinoside in PML may have been the consequence of inadequate penetration of the drug to sites of infection in the brain. Other drugs with established in vitro activity against JC virus, such as topoisomerase and camptothecin, are poorly tolerated. The use of cidofovir in patients with AIDS and PML remains anecdotal, although it is currently under investigation. Interferon alfa may improve survival in patients with AIDS and PML and may have general applicability to PML regardless of the cause of the underlying immunodeficient state. Approximately 7% to 9% of patients with PML demonstrate prolonged survival (>12 months) and associated improvement in clinical and radiographic abnormalities in the absence of specific therapy. In patients with AIDS-related PML, prolonged survival correlates with PML as the presenting manifestation of AIDS, higher CD4 T-lymphocyte counts, and contrast enhancement of PML lesions on radiographic imaging. A brisk inflammatory response may also be associated with improved survival. The increased understanding of the pathophysiology of JC virus provides hope for the development of curative strategies. The growing number of persons affected with PML has allowed the organization of carefully designed therapeutic trials to address this issue.
 ...
PMID:Progressive Multifocal Leukoencephalopathy. 1109 61

Acute myeloid leukaemia (AML) is characterized by a block in differentiation and an unregulated proliferation of myeloid progenitor cells. While the cause of AML in children is unknown, risk factors that have been identified include exposure to toxins such as ethanol, pesticides and dietary topoisomerase II inhibitors, prior chemotherapy with alkylating agents or topoisomerase II inhibitors, constitutional disorders such as Down's syndrome and type I neurofibromatosis, and haematopoietic failure syndromes such as Fanconi anaemia and severe congenital neutropenia. With intensified chemotherapy including high-dose Ara-C, followed in many cases by bone marrow transplantation, and with improvements in supportive care, current survival rates approach 50%. Future advances in paediatric AML will include better risk stratification to determine optimal treatment and targeted cytotoxic therapy.
 ...
PMID:Acute myeloid leukaemia in children. 1135 25

Cytosine arabinoside (cytarabine or Ara-C) has been one of the cornerstones of treatment of acute myeloid leukemia since its approval in 1969. Standard induction therapy worldwide for all patients deemed fit for treatment (excluding those with acute promyelocytic leukemia) remains unchanged for over 40 years and consists of Ara-C administered by continuous infusion in combination with a topoisomerase II inhibitor (e.g., daunorubicin, idarubicin and mitoxantrone). Despite decades of clinical investigation, the optimum dose of both agents still remains unclear. Although higher doses of Ara-C have been shown to improve response rates, the elderly poorly tolerate these regimens. Resistance mechanisms also develop or may be present at diagnosis resulting in poor outcomes. Elacytarabine (CP-4055), an elaidic acid ester of Ara-C, has been developed using lipid vector technology in an attempt to overcome these limitations. Clinical data are encouraging, with evidence suggesting that this novel agent is circumventing resistance mechanisms but retaining the potent antileukemic efficacy of Ara-C.
 ...
PMID:Elacytarabine: lipid vector technology under investigation in acute myeloid leukemia. 2337 75

Chemotherapy remains mainly used for the treatment of acute myeloid leukemia (AML). However, in the past 3 decades limited progress has been achieved in improving the long-term disease-free survival. Therefore the development of more effective drugs for AML represents a high level of priority. F14512 combines an epipodophyllotoxin core targeting topoisomerase II with a spermine moiety introduced as a cell delivery vector. The polyamine moiety facilitates F14512 selective uptake by tumour cells via the polyamine transport system, a machinery overactivated in cancer cells. F14512 has been characterized as a potent drug candidate and is currently in Phase I clinical trials. Here, we demonstrated marked survival benefit and therapeutic efficacy of F14512 treatments in a series of human AML models, established either from AML cell lines or from patient AML samples. Furthermore, we reported in vitro synergistic anti-leukemic effects of F14512 in combination with cytosine arabinoside (Ara-C), doxorubicin, gemcitabine, bortezomib or SAHA. In vivo combination of suboptimal doses of F14512 with Ara-C also resulted in enhanced anti-leukemic activity. We further showed that F14512 triggered both senescence and apoptosis in vivo in primary AML models, but not autophagy. Overall, these results support the clinical development in onco-hematology of this novel promising drug candidate.
 ...
PMID:F14512, a polyamine-vectorized anti-cancer drug, currently in clinical trials exhibits a marked preclinical anti-leukemic activity. 2356 48


<< Previous 1 2