Deoxyribonucleic acid (DNA) and deoxynucleotide (dNTP) pools (DNA/dNTP pools)

Deoxyribonucleic acid (DNA) and the intracellular pools of deoxynucleoside triphosphates (dNTPs) are fundamental targets in the treatment of cancer and viral infections [1, 4]. The dNTP pool, consisting of dATP, dGTP, dCTP, and dTTP, provides the necessary precursors for DNA synthesis and repair, and its balance is maintained by enzymes such as ribonucleotide reductase (RNR) and SAMHD1 [2, 10]. Disrupting this balance or directly damaging the DNA structure leads to replication stress, genomic instability, and eventually programmed cell death [1, 6]. Antimetabolite drugs like gemcitabine and 5-fluorouracil act by inhibiting dNTP synthesis or incorporating into DNA as fraudulent bases, while alkylating agents and platinum compounds create covalent adducts that block replication forks [6, 17]. Modern therapeutic strategies also include PARP inhibitors, which target the DNA repair machinery to induce synthetic lethality in cells with existing genetic defects [4, 13]. Understanding the dynamics of these pools and the structural integrity of DNA is essential for developing effective chemotherapies and monitoring treatment response through various molecular biomarkers [7, 16].

Other names

DNAdNTP poolsDeoxynucleoside triphosphate poolsGenomic DNADeoxyribonucleotide pools

Drugs targeting DNA and deoxynucleotide pools operate through several distinct mechanisms: inhibition of de novo dNTP biosynthesis (e.g., via ribonucleotide reductase or thymidylate synthase inhibition), competitive inhibition of DNA polymerases by nucleoside analogs, direct covalent modification of DNA (alkylation and cross-linking), and inhibition of DNA topoisomerases or repair enzymes like PARP [1, 4, 6, 13]. These actions collectively lead to the depletion of essential building blocks, the introduction of lethal DNA lesions, and the stalling of replication forks, ultimately triggering apoptosis in rapidly proliferating cells [9, 17].