Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026986 (myelodysplastic syndrome)
 14,926 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mechanism of clinical action for the FDA approved hypomethylating drugs azacitidine and decitabine remains unresolved and in this context the potential immunomodulatory effect of these agents on leukemic cells is an area of active investigation. Induced expression of methylated Cancer Testis Antigen (CTA) genes has been demonstrated in leukemic cell lines following exposure to hypomethylating drugs in vitro. SGI-110 is a novel hypomethylating dinucleotide with prolonged in vivo exposure and clinical activity in patients with MDS and AML. We demonstrate that this agent, like decitabine, produces robust re-expression of the CTAs NY-ESO-1 and MAGE-A, both in vitro and in leukemia-bearing AML xenografts. Upregulation of these genes in vitro was sufficient to induce cytotoxicity by HLA-compatible CD8+ T-cells specific for NY-ESO-1, a well-recognized and immunogenic CTA. Additionally, exposure to SGI-110 enhances MHC class I and co-stimulatory molecule expression, potentially contributing to recognition of CTAs. SGI-110, like the parent compound decitabine, induces expression of CTAs and might modulate immune recognition of myeloid malignancy.
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PMID:Immunomodulatory action of SGI-110, a hypomethylating agent, in acute myeloid leukemia cells and xenografts. 2526 Aug 25

SGI-110 is a second-generation hypomethylating prodrug whose active metabolite is the well-characterized drug decitabine. This novel compound is an oligonucleotide consisting of decitabine linked through a phosphodiester bond to the endogenous nucleoside deoxyguanosine. The dinucleotide configuration provides protection from drug clearance by deamination, while maintaining at least equivalent effects on gene-specific and global hypomethylation both in vitro and in animal model systems. This agent is currently being tested in phase I and II clinical trials in humans and has been demonstrated to be safe and well tolerated as a single agent, with evidence of promising activity in heavily pretreated (including currently FDA approved hypomethylating drugs) myelodysplastic syndrome and acute myeloid leukemia patients. Ongoing trials are also open in platinum-resistant ovarian cancer and hepatocellular carcinoma.
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PMID:SGI-110: DNA Methyltransferase Inhibitor Oncolytic. 2619 Aug 89

Recent advances in drug treatment for higher-risk myelodysplastic syndromes (MDS) have focused on DNA hypomethylating agents (HMAs). Azacitidine (AZA), a representative HMA available in Japan, has demonstrated a survival benefit over conventional treatment. However, unsatisfactory treatment profiles of AZA exemplified by a low response rate of <20% complete remission (CR), a short duration of response (usually <1 year), and dismal outcomes after the failure to fulfil unmet needs in AZA treatments have highlighted the urgent need for the development of novel therapeutic modalities. In this manuscript, an array of novel agents under clinical investigation for higher-risk MDS is introduced. The drugs in the most advanced phase of development include SGI-110, a next-generation DNA hypomethylating agent that is designed to prolong cellular exposure time, and the multi-kinase inhibitor rigosertib, which is specifically active against patients with higher-risk MDS who fail to respond to conventional HMAs. Other lines of agents under investigation include a combination of histone deacetylase inhibitors and hypomethylating agents, immune checkpoint inhibitors, spliceosome inhibitors, BCL2 inhibitors, and IDH1/2 inhibitors, all of which have been developed by exploiting the recent understanding of the molecular pathogenesis of MDS, including the tumorigenic role of common mutations and disturbance of tumor immunity.
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PMID:[Novel therapies for higher-risk myelodysplastic syndromes]. 3030 9

High-risk myelodysplastic syndrome/acute myeloid leukemia patients have a very poor survival after azacitidine failure. Guadecitabine (SGI-110) is a novel subcutaneous hypomethylating agent which results in extended decitabine exposure. This multicenter phase II study evaluated the efficacy and safety of guadecitabine in high-risk myelodysplastic syndrome and low blast count acute myeloid leukemia patients refractory or relapsing after azacitidine. We included 56 patients with a median age of 75 years [Interquartile Range (IQR) 69-76]. Fifty-five patients received at least one cycle of guadecitabine (60 mg/m2/d subcutaneously days 1-5 per 28-day treatment cycles), with a median of 3 cycles (range, 0-27). Eight (14.3%) patients responded, including two complete responses; median response duration was 11.5 months. Having no or few identified somatic mutations was the only factor predicting response (P=0.035). None of the 11 patients with TP53 mutation responded. Median overall survival was 7.1 months, and 17.9 months in responders (3 of whom had overall survival >2 years). In multivariate analysis, IPSS-R (revised International Prognostic Scoring System) score other than very high (P=0.03) primary versus secondary azacitidine failure (P=0.01) and a high rate of demethylation in blood during the first cycle of treatment (P=0.03) were associated with longer survival. Thus, guadecitabine can be effective, sometimes yielding relatively prolonged survival, in a small proportion of high-risk myelodysplastic syndrome/low blast count acute myeloid leukemia patients who failed azacitidine. (Trial registered at clinicaltrials.gov identifier: 02197676).
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PMID:A phase II study of guadecitabine in higher-risk myelodysplastic syndrome and low blast count acute myeloid leukemia after azacitidine failure. 3073 71