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Experimental therapy with 9-[2-(phosphonomethoxy)ethyl]-2,6-diaminopurine (PMEDAP): origin of resistance

M Zápotocký1, J Hanzalová, J Starková

  • 1Department of Paediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University, Prague, Czech Republic. Michal.Zapotocky@fnmotol.cz

Folia Biologica
|June 21, 2007
PubMed

Insights

Multidrug resistance-associated protein 4 (MRP4) and MRP5 transporters contribute to resistance against the chemotherapy drug PMEDAP. Their combined action drives the development of drug resistance in cancer cells.

Area of Science:

  • Pharmacology
  • Molecular Biology
  • Cancer Research

Background:

  • Acyclic nucleoside phosphonates, such as PMEDAP, are used as cytostatic agents in cancer therapy.
  • Drug resistance is a major challenge in cancer treatment, limiting the efficacy of chemotherapeutic agents.
  • Multidrug resistance-associated proteins (MRPs) are known to be involved in the efflux of various drugs from cells.

Purpose of the Study:

  • To investigate the role of MRP4 and MRP5 transporters in the cellular efflux and resistance to the acyclic nucleoside phosphonate PMEDAP.
  • To elucidate the distinct and cooperative roles of MRP4 and MRP5 in the development of PMEDAP resistance.
  • To study the expression patterns of MRP4 and MRP5 genes during long-term PMEDAP treatment.

Main Methods:

  • In vitro studies using CCRF-CEM cells to assess PMEDAP efflux and transporter function.
  • In vivo studies utilizing spontaneous transplantable T-cell lymphoma in SD/Cub inbred rats.
  • Gene expression analysis to quantify the levels of MRP4 and MRP5 mRNA during treatment.

Main Results:

  • Increased resistance to PMEDAP was observed with long-term treatment, correlating with the overexpression of MRP4 and MRP5 genes.
  • MRP5 function was found to be crucial for the initial development of PMEDAP resistance.
  • MRP4 gene expression increased more continuously throughout the treatment period, suggesting a progressive role.

Conclusions:

  • Both MRP4 and MRP5 transporters play a significant role in mediating resistance to PMEDAP.
  • The development of PMEDAP resistance involves a cooperative action between MRP4 and MRP5.
  • Understanding the distinct activation patterns of MRP4 and MRP5 can inform strategies to overcome drug resistance in cancer therapy.

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