Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.5.1.1 (asparaginase)
 2,695 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The major established cause of acute myeloid leukemia (AML) in the young is cancer chemotherapy. There are two forms of treatment-related AML (t-AML). Each form has a de novo counterpart. Alkylating agents cause t-AML characterized by antecedent myelodysplasia, a mean latency period of 5-7 years and complete or partial deletion of chromosome 5 or 7. The risk is related to cumulative alkylating agent dose. Germline NF-1 and p53 gene mutations and the GSTT1 null genotype may increase the risk. Epipodophyllotoxins and other DNA topoisomerase II inhibitors cause leukemias with translocations of the MLL gene at chromosome band 11q23 or, less often, t(8;21), t(3;21), inv(16), t(8;16), t(15;17) or t(9;22). The mean latency period is about 2 years. While most cases are of French-American-British (FAB) M4 or FAB M5 morphology, other FAB AML subtypes, myelodysplastic syndrome (MDS), acute lymphoblastic leukemia (ALL) and chronic myelogenous leukemia (CML) occur. Between 2 and 12% of patients who receive epipodophyllotoxin have developed t-AML. There is no relationship with higher cumulative epipodophyllotoxin dose and genetic predisposition has not been identified, but weekly or twice-weekly schedules and preceding l-asparaginase administration may potentiate the risk. The translocation breakpoints in MLL are heterogeneously distributed within a breakpoint cluster region (bcr) and the MLL gene translocations involve one of many partner genes. DNA topoisomerase II cleavage assays demonstrate a correspondence between DNA topoisomerase II cleavage sites and the translocation breakpoints. DNA topoisomerase II catalyzes transient double-stranded DNA cleavage and rejoining. Epipodophyllotoxins form a complex with the DNA and DNA topoisomerase II, decrease DNA rejoining and cause chromosomal breakage. Furthermore, epipodophyllotoxin metabolism generates reactive oxygen species and hydroxyl radicals that could create abasic sites, potent position-specific enhancers of DNA topoisomerase II cleavage. One proposed mechanism for the translocations entails chromosomal breakage by DNA topoisomerase II and recombination of DNA free ends from different chromosomes through DNA repair. With few exceptions, treatment-related leukemias respond less well to either chemotherapy or bone marrow transplantation than their de novo counterparts, necessitating more innovative treatments, a better mechanistic understanding of the pathogenesis, and strategies for prevention.
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PMID:Secondary leukemias induced by topoisomerase-targeted drugs. 974 98

The essential oil (EO) composition of the aerial parts of Erigeron multiradiatus (Lindl.ex DC.) Benth growing wild in the central Himalayan region of Uttarakhand, India, was analyzed by capillary gas chromatography with a flame ionization detector and gas chromatography-mass spectrometry. A sum of 12 constituents was identified, representing 97.81% of the oil composition. The oil was composed mainly of oxygenated monoterpenes (88.95%), sesquiterpene hydrocarbons (5.61%), oxygenated sesquiterpenes (3.05%), and monoterpene hydrocarbons (0.20%). Major constituents identified were trans-2-cis-8-matricaria-ester (77.79%), cis-lachnophyllum ester (11.04%), zingiberene (4.43%), and spathulenol (1.59%). Further, the leishmanicidal effect of EO and the purified compound trans-2-cis-8-matricaria-ester has been investigated against Leishmania donovani promastigotes and intracellular amastigotes. EO and trans-2-cis-8-matricaria-ester were safer for the hamster peritoneal macrophage and lethal to promastigotes and intracellular amastigotes at different concentrations. Further, using an in silico approach, these four compounds were tested against 10 major proteins of L. donovani associated with its virulence. Out of them, only trans-2-cis-8-matricaria-ester was found to be effective against the four target proteins, namely, l-asparaginase-1-like protein, metacaspase 2, metacaspase 1, and DNA topoisomerase II of L. donovani. The results indicate that EO contains trans-2-cis-8-matricaria-ester as a major component and showed antileishmanial activity which may facilitate discovery of new lead molecules for developing herbal medicines against visceral leishmaniasis.
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PMID:Identification of trans-2-cis-8-Matricaria-ester from the Essential Oil of Erigeron multiradiatus and Evaluation of Its Antileishmanial Potential by in Vitro and in Silico Approaches. 3152 20