Experimental Therapy with 9-[2-(Phosphonomethoxy)ethyl]-2,6-diaminopurine (PMEDAP): Origin of Resistance

Zápotocký, Michal; Hanzalová, J.; Starková, J.; Votruba, I.; Holý, A.; Otová, Berta

doi:10.14712/fb2007053030079

Fol. Biol. 2007, 53, 79-84

https://doi.org/10.14712/fb2007053030079

Experimental Therapy with 9-[2-(Phosphonomethoxy)ethyl]-2,6-diaminopurine (PMEDAP): Origin of Resistance

Michal Zápotocký^1,2, J. Hanzalová², J. Starková¹, I. Votruba³, A. Holý³, Berta Otová²

¹Department of Paediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University, Prague, Czech Republic
²Institute of Biology and Medical Genetics, 1st Faculty of Medicine and General Teaching Hospital, Charles University, Prague, Czech Republic
³Centre for New Antivirals and Antineoplastics, Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Prague, Czech Republic

Received February 2007
Accepted April 2007

The role of MRP4 and MRP5 transporters in the acyclic nucleoside phosphonate PMEDAP efflux was studied in vitro (CCRF-CEM cells) and in vivo (spontaneous transplantable T-cell lymphoma of SD/Cub inbred rats). The increased resistance against the cytostatic agent PMEDAP during long-term treatment was found to be associated with over-expression of MRP4 and MRP5 genes. The course of both gene activation differs significantly. While the MRP5 function is important in the onset of PMEDAP resistance, the intensity of the relative MRP4 gene expression increases rather continuously. Our data indicate cooperative acting of both MRP4 and MRP5 genes during the PMEDAP resistance development.