The effect of new antitumor agents on the energy metabolism of human erythrocytes.

Robert Nowak1, Irena Baranowska-Bosiacka1, Barbara Stefanska2, Alina Joanna Hlynczak1, Jolanta Tarasiuk1, 2

1 Department of Biochemistry, University of Szczecin, Poland 2 Department of Pharmaceutical Technology and Biochemistry, Technical University of Gdansk, Poland

The ability of neoplastic cells to develop multidrug resistance is the serious problem in the clinic, because it results in a wild range spectrum of resistance to drugs that show little structural similarity and different mechanisms of action. For this reason the search for new antitumor agents enables to overcome multidrug resistance is of prime importance. Multidrug resistance phenotype is related with the overexpression of ATP-dependent drug efflux pumps (e.g. P-glycoprotein, MRP1-multidrug resistance-associated protein) responsible for the reduction of the intracellular accumulation and hence for the marked decrease in the cytotoxicity of antitumor agents used in the clinic (eg. anthracyclines - doxorubicin, daunorubicin; vinca alkaloids - vincristine, vinblasine; podophylotoxins). Recently we obtained some new groups of cytostatic (e.g. benzoperimidines, anthrapyridones) able to overcome multidrug resistance of tumor cells. These agents had very fast kinetics of cellular uptake which counterbalance their efflux by ATP-dependent exporting pumps. It could disturb an energy metabolism of tumor as well as normal cells. It is well known that erythrocytes have relatively high level of MRP1 and MRP5 proteins. The aim of this study was to examine the effect of new selected benzopyrimidines and anthrapyridones antitumour agents on the energy metabolism of erythrocytes isolated from whole human blood. Adenylate energy charge (AEC) is the most important factor describing the energy state of the cell. It influences many catabolic and anabolic processes regulation. AEC value and purine concentration (ATP, ADP, AMP, Ado, GTP, GDP, GMP, Guo, IMP, Ino, Hyp, Xan, UA, NAD, NADP) have been determined using HPLC method. In our study we used modified method of Smolenski (Smolenski, 1990, J. Chrom. 527, 414-420) - the reference method for purines determination.

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Multidrug Resistance - MDR.