Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

DNA methyltransferase (DNMT) inhibitors, azacitidine (Vidaza, Pharmion, Boulder, CO, USA) and decitabine (Dacogen; SuperGen Inc, Dublin, CA, USA, and MGI Pharma Inc, Bloomington, MN, USA), have had a significant impact on the treatment paradigm of myelodysplastic syndromes (MDSs), previously managed mainly by supportive care and hematopoietic-stem-cell transplantation. The positive clinical experience seen in MDS to date coupled with the persistent challenges faced in the treatment of other hematologic malignancies has served as the impetus for further exploration of the therapeutic value of DNMT inhibitors beyond MDS. In that respect, the majority of data for these agents are in the setting of acute myelogenous leukemia (AML). Experience with these agents in patients with refractory anemia with excess blasts in transformation (reclassified by the World Health Organization as AML) was also reported in the clinical trials submitted to the FDA for approval of azacitidine for MDS. Some use has also been described in chronic myelogenous leukemia and acute lymphocytic leukemia. Further studies are needed to clarify the appropriate dose and the number and duration of cycles in the treatment of leukemias, and to identify ideal candidates for therapy, explore the role of DNMT inhibitors in combination with other agents, especially histone deacetylase inhibitors, delineate differences between the commercially available agents, and establish the long-term safety of these agents. To this end, experience with DNMT inhibitors in hematologic malignancies other than MDS is reviewed in an effort to better understand the therapeutic potential of these agents and to define areas of future exploration in these settings.
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PMID:Inhibitors of DNA methylation: beyond myelodysplastic syndromes. 1634 Dec 39

Methylation of DNA at 5-position of cytosine, catalyzed by DNA methyltransferases, is the predominant epigenetic modification in mammals. Aberrations in methylation play a causal role in a variety of diseases, including cancer. Recent studies have established that like mutation, methylation-mediated gene silencing often leads to tumorigenesis. Paradoxically, genome-wide DNA hypomethylation may also play a causal role in carcinogenesis by inducing chromosomal instability and spurious gene expression. Since methylation does not alter DNA base sequence, much attention has been focused recently on developing small molecule inhibitors of DNA methyltransferases that can potentially be used as anticancer agents. Vidaza (5-azacytidine), marketed by Pharmion (Boulder, CO, USA), was the first DNA methyltransferase inhibitor approved by the U.S. Food and Drug Administration (FDA) for chemotherapy against myelodysplastic syndrome (MDS), a heterogeneous bone marrow disorder. Recently MGI Pharma Inc. (Bloomington, MN, USA) got FDA approval to market Dacogen (5-aza-2'-deoxycytidine, or decitabine) for treating MDS patients. These drugs were used earlier against certain anemias to induce expression of fetal globin genes. Interest in clinical trials of these drugs as anticancer agents has been renewed only recently because of reversal of methylation-mediated silencing of critical genes in cancer. Clinical trials have shown that both drugs have therapeutic potential against leukemia such as MDS, acute myeloid leukemia, chronic myelogenous leukemia and chronic myelomonocytic leukemia. In contrast, their effectiveness with solid tumors appears to be less promising, which challenges researchers to develop inhibitors with more efficacy and less toxicity. The major hindrance of their usage as anticancer agents is their instability in vivo as well as the toxicity secondary to their excessive incorporation into DNA, which causes cell cycle arrest. Gene expression profiling in cancer cells revealed that antineoplastic property of these drugs is mediated through both methylation-dependent and -independent pathways. Recently, we have shown that treatment of cancer cells with these cytidine analogues also induces proteasomal degradation of DNA methyltransferase 1, the ubiquitously expressed enzyme upregulated in almost all cancer cells. Development of related stable drugs that can facilitate gene activation in cancer cells by enhancing degradation of DNA methyltransferases without being incorporated into DNA would be ideal for chemotherapy. In this monograph we review historical perspective and recent advances on the molecular mechanisms of action and clinical applications of these DNA hypomethylating agents.
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PMID:DNA methyltransferases as targets for cancer therapy. 1761 10

The pyrimidine analogs, 5-azacytidine (azacitidine, Vidaza) and its deoxy derivative, 5-aza-2'-deoxycytidine (decitabine, Dacogen, are the most widely used inhibitors of DNA methylation which trigger demethylation leading to a consecutive reactivation of epigenetically silenced tumor suppressor genes in vitro and in vivo. Although the antileukemic capacity of decitabine has been known for almost 40 years, its therapeutic potential in hematologic malignancies is still under intensive investigation. Multiple clinical trials have shown the promising activity of low-dose decitabine in AML, MDS, CML, and hemoglobinopathies, whereas its efficacy in solid tumors is rather limited.Clinical responses appear to be induced by both epigenetic alterations and the induction of cell-cycle arrest and/or apoptosis. Recent clinical trials have been investigating new dosing schedules, routes of administration, and combination of decitabine with other agents, including histone deacetylase (HDAC) inhibitors.
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PMID:Decitabine. 2007 36

We report the case of an otherwise healthy 60-year-old man presenting with fever, leucocytosis and a painful swelling of the right calf. We initially performed cultural and cytological examination of the popliteal fossa mass, but the results were disappointingly inconclusive. The subsequent development of several erythematous subcutaneous nodules, rapidly evolving to broad ulcerative lesions, prompted us to reconsider the clinical setting as a whole, which included fever, marked leucocytosis and multiple subcutaneous nodules. A biopsy of the ulcerative lesions finally led to the diagnosis of neutrophilic panniculitis, which was sustained by a hybrid myelodysplastic/myeloproliferative disorder like BCR-ABL1-negative atypical chronic myeloid leukaemia. The patient was initially treated with high-dose intravenous corticosteroids, resulting in a dramatic improvement of the skin lesions and normalisation of blood tests. Azacytidine treatment was subsequently started, and the haematological disease remained stable.
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PMID:Atypical neutrophilic panniculitis as presentation of BCR-ABL1-negative chronic myeloid leukaemia. 3159 85