Therapy related disturbances in nucleotides in cancer cells.

Abstract

Ribonucleotides (NTP) and deoxyribonucleotides (dNTP) form the end products of the purine and pyrimidine synthetic pathways, both the de novo and the salvage pathways. They form the direct substrates for RNA and DNA synthesis. Nucleotide pools in the cell are the result of a dynamic equilibrium of synthesis and consumption. Besides their essential role in nucleic acid synthesis, ribonucleotides are essential for a number of other functions in the cell such as a source for energy supply (ATP), nucleotide sugar synthesis (UTP, CTP and GTP), lipid biosynthesis (CTP), signal transduction (ATP, GTP as part of the GTP binding protein, cyclic nucleotides such as cAMP and cGMP), protein elongation, tubulin-binding and ras-oncogene (all GTP), phosphate donors for kinase catalyzed reactions (mostly ATP, but other nucleotides can also act as a phosphate donor), allosteric activators and feedback regulators of several synthetic pathways, co-enzyme in several synthetic reactions such folyl-polyglutamate synthetase and phosphoribosylpyrophosphate (PRPP) synthetase. Besides being a substrate for DNA synthesis, dNTP play an essential role in DNA repair and as feedback regulators of a number of enzymes. E.g. dTTP is an inhibitor of dCMP deaminase [1], and of thymidine kinase [2]; dATP is a potent feedback inhibitor of ribonucleotide reductase [3, 4], inhibiting the synthesis of all deoxyribonucleoside diphosphates, dGTP that of dGDP, dUDP and dCDP, dTTP that of dUDP and dCDP, while ATP is an activator of this enzyme, and dTTP an activator of the reduction of GDP to dGDP and dGTP of that of ADP to dADP. Thus, any perturbation of the synthesis or use of both NTP and dNTP can have major effects on cellular functioning. Thus measurement of nucleotide pools in cells during exposure to any drug and especially to drugs directed against synthesis of (deoxy)ribonucleotides can give essential information on the mechanism of action of these drugs.KeywordsRibonucleotide ReductaseNucleotide PoolDeoxycytidine KinaseSolid Tumor Cell LinedNTP PoolThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.