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

0360711 - ÚOCHB 2012 RIV US eng J - Journal Article
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. E-ISSN 1873-2968
R&D Projects: GA MŠMT 1M0508
Institutional research plan: CEZ:AV0Z40550506
Keywords : resistance * acyclic nucleoside phosphonates * PMEG * PMEDAP
Subject RIV: CE - Biochemistry
Impact factor: 4.705, year: 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.
Permanent Link: http://hdl.handle.net/11104/0198197