About: Mutations in Adenosine Deaminase-like (ADAL) Protein Confer Resistance to the Antiproliferative Agents N-6-Cyclopropyl-PMEDAP and GS-9219

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About: Mutations in Adenosine Deaminase-like (ADAL) Protein Confer Resistance to the Antiproliferative Agents N-6-Cyclopropyl-PMEDAP and GS-9219 Goto Sponge NotDistinct Permalink

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rdf:type	skos:Concept http://linked.opendata.cz/ontology/domain/vavai/Vysledek
Description	Background/Aim: GS 9219 is a double prodrug of antiproliferative nucleotide analog 9-(2-Phosphonylmethoxyethyl)guanine (PMEG), with potent in vivo efficacy against various hematological malignancies. This study investigates the role of adenosine deaminase-like (ADAL) protein in the intracellular activation of GS-9219. Materials and Methods: A cell line resistant to 9-(2-Phosphonylmethoxyethyl)-N-6-cyclopropyl-2,6-diaminopurine (cPrPMEDAP), an intermediate metabolite of GS-9219, was generated and characterized. Results: The resistant cell line was cross-resistant to cPrPMEDAP and GS-9219, due to a defect in the deamination of cPrPMEDAP to PMEG. Mutations in the ADAL gene (H286R and S180N) were identified in the resistant cells that adversely-affected its enzymatic activity. Introduction of the wild-type ADAL gene re-sensitized resistant cells to both cPrPMEDAP and GS-9219. Conclusion: The ADAL protein plays an essential role in the intracellular activation of GS-9219 by catalyzing the deamination of cPrPMEDAP metabolite to PMEG. Mutations affecting the activity of ADAL confer resistance to both GS-9219 and its metabolite cPrPMEDAP. Background/Aim: GS 9219 is a double prodrug of antiproliferative nucleotide analog 9-(2-Phosphonylmethoxyethyl)guanine (PMEG), with potent in vivo efficacy against various hematological malignancies. This study investigates the role of adenosine deaminase-like (ADAL) protein in the intracellular activation of GS-9219. Materials and Methods: A cell line resistant to 9-(2-Phosphonylmethoxyethyl)-N-6-cyclopropyl-2,6-diaminopurine (cPrPMEDAP), an intermediate metabolite of GS-9219, was generated and characterized. Results: The resistant cell line was cross-resistant to cPrPMEDAP and GS-9219, due to a defect in the deamination of cPrPMEDAP to PMEG. Mutations in the ADAL gene (H286R and S180N) were identified in the resistant cells that adversely-affected its enzymatic activity. Introduction of the wild-type ADAL gene re-sensitized resistant cells to both cPrPMEDAP and GS-9219. Conclusion: The ADAL protein plays an essential role in the intracellular activation of GS-9219 by catalyzing the deamination of cPrPMEDAP metabolite to PMEG. Mutations affecting the activity of ADAL confer resistance to both GS-9219 and its metabolite cPrPMEDAP. (en)
Title	Mutations in Adenosine Deaminase-like (ADAL) Protein Confer Resistance to the Antiproliferative Agents N-6-Cyclopropyl-PMEDAP and GS-9219 Mutations in Adenosine Deaminase-like (ADAL) Protein Confer Resistance to the Antiproliferative Agents N-6-Cyclopropyl-PMEDAP and GS-9219 (en)
skos:prefLabel	Mutations in Adenosine Deaminase-like (ADAL) Protein Confer Resistance to the Antiproliferative Agents N-6-Cyclopropyl-PMEDAP and GS-9219 Mutations in Adenosine Deaminase-like (ADAL) Protein Confer Resistance to the Antiproliferative Agents N-6-Cyclopropyl-PMEDAP and GS-9219 (en)
skos:notation	RIV/61388963:_____/13:00393845!RIV14-AV0-61388963
http://linked.open...avai/predkladatel	Ústav organické chemie a biochemie AV ČR, v. v. i.
http://linked.open...avai/riv/aktivita	I
http://linked.open...avai/riv/aktivity	I
http://linked.open...iv/cisloPeriodika	5
http://linked.open...vai/riv/dodaniDat	2014
http://linked.open...aciTvurceVysledku	Votruba, Ivan
http://linked.open.../riv/druhVysledku	J - Článek v odborném periodiku
http://linked.open...iv/duvernostUdaju	S - Úplné a pravdivé údaje nepodléhající ochraně podle zvláštních právních předpisů
http://linked.open...titaPredkladatele	Ústav organické chemie a biochemie AV ČR, v. v. i.
http://linked.open...dnocenehoVysledku	90240
http://linked.open...ai/riv/idVysledku	RIV/61388963:_____/13:00393845
http://linked.open...riv/jazykVysledku	eng - angličtina
http://linked.open.../riv/klicovaSlova	ADAL; deamination; GS-9219; PMEG (en)
http://linked.open.../riv/klicoveSlovo	ADAL deamination GS-9219 PMEG
http://linked.open...odStatuVydavatele	GR - Řecká republika
http://linked.open...ontrolniKodProRIV	[97287C0CBE02]
http://linked.open...i/riv/nazevZdroje	Anticancer Research
http://linked.open...in/vavai/riv/obor	CE
http://linked.open...ichTvurcuVysledku	1 (xsd:int)
http://linked.open...cetTvurcuVysledku	13 (xsd:int)
http://linked.open...UplatneniVysledku	2013
http://linked.open...v/svazekPeriodika	33
http://linked.open...iv/tvurceVysledku	Andrei, G. Cihlar, T. Snoeck, R. Votruba, Ivan Cannizzaro, C. Fiten, P. Frey, C. R. Fung, W. C. Geleziunas, R. Han, B. Hung, M. Liu, X. H. Opdenakker, G.
http://linked.open...ain/vavai/riv/wos	000319233100016
issn	0250-7005
number of pages	13 (xsd:int)

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