Cellular Deoxyribonucleic Acid and Ribonucleic Acid (DNA/RNA)

Cellular deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) serve as the primary therapeutic targets for thiopurine antimetabolites, including 6-thioguanine and 6-mercaptopurine. These drugs are converted intracellularly into 6-thioguanine nucleotides (6-TGNs), which act as fraudulent building blocks during nucleic acid synthesis. When 6-TGNs are incorporated into DNA, they pair incorrectly with cytosine or are methylated to 6-methylthioguanine, which pairs with thymine, triggering the post-replicative mismatch repair (MMR) system. This process leads to the generation of DNA gaps, double-strand breaks, and ultimately programmed cell death or apoptosis (PubMed: 15761452; NIH StatPearls: NBK557559). \n\nIn addition to DNA effects, 6-TGN incorporation into RNA disrupts the processing, stability, and translation of various RNA species, contributing to the inhibition of protein synthesis and cell proliferation. This dual targeting of DNA and RNA is particularly effective against rapidly dividing cells, such as malignant leukocytes in leukemia or activated T-cells in autoimmune conditions like inflammatory bowel disease. Monitoring of 6-TGN levels and genetic testing for enzymes like TPMT and NUDT15 are critical for managing the narrow therapeutic index and avoiding severe myelosuppression associated with this target (PharmGKB: PA166123139). Overall, the incorporation of 6-thioguanine into nucleic acids remains a cornerstone of chemotherapy and immunosuppression.

Other names

Genomic DNACellular RNA6-TGN-incorporated nucleic acidsThioguanine-modified DNA

Metabolic conversion of thiopurine prodrugs into 6-thioguanine nucleotides (6-TGNs) followed by their incorporation into DNA and RNA, which triggers mismatch repair-mediated apoptosis and inhibits protein synthesis (StatPearls: NBK557559; PubMed: 15761452).