Počet záznamů: 1

Point mutations in human guanylate kinase account for acquired resistance to anticancer nucleotide analogue PMEG

  1. 1.
    0360711 - UOCHB-X 2012 RIV US eng J - Článek v odborném periodiku
    Mertlíková-Kaiserová, Helena - Rumlová, Michaela - Tloušťová, Eva - Procházková, Eliška - Holý, Antonín - Votruba, Ivan
    Point mutations in human guanylate kinase account for acquired resistance to anticancer nucleotide analogue PMEG.
    Biochemical Pharmacology. Roč. 82, č. 2 (2011), s. 131-138 ISSN 0006-2952
    Grant CEP: GA MŠk 1M0508
    Výzkumný záměr: CEZ:AV0Z40550506
    Klíčová slova: resistance * acyclic nucleoside phosphonates * PMEG * PMEDAP
    Kód oboru RIV: CE - Biochemie
    Impakt faktor: 4.705, rok: 2011

    The ability of a nucleotide analogue PMEG to induce resistance and the mechanisms involved were adressed. CCRF-CEM cells resistant to either PMEG or its congener PMEDAP were assayed for the expression of membrane transporters, PMEG and PMEDAP uptake and metabolism. PMEG phosphorylation to PMEG mono- and diphosphate was completely impaired in resistant cells. Guanylate kinase (GUK) obtained from PMEG-resistant cells revealed two point mutations S(35)N V(168)F that significantly suppressed its catalytic activity. Transfection with wtGUK led to the recovery of phosphorylating activity and sensitivity towards PMEG cytotoxicity. Primary sequence of adenylate kinase (AK) from PMEDAP resistant cells was unaffected. Resistance induced by PMEDAP is thus conferred by other mechanisms. No differences in PMEG uptake have been found between sensitive and resistant cells. GUK was identified as the sole molecular target for the development of resistance to PMEG.
    Trvalý link: http://hdl.handle.net/11104/0198197