DNA containing gemcitabine triphosphate (dFdCTP-DNA) (dFdCTP-DNA)

Gemcitabine triphosphate (dFdCTP) is the active cytotoxic metabolite of the nucleoside analog gemcitabine (StatPearls, https://www.ncbi.nlm.nih.gov/books/NBK499853/). It serves as a fraudulent substrate for DNA polymerases, competing with the natural nucleotide deoxycytidine triphosphate (dCTP) for incorporation into the growing DNA strand during replication (PubChem, https://pubchem.ncbi.nlm.nih.gov/compound/Gemcitabine). Once dFdCTP is incorporated, DNA polymerase adds exactly one additional natural deoxynucleotide before DNA synthesis is halted, a unique process known as "masked chain termination" (Plunkett et al., 1995, https://pubmed.ncbi.nlm.nih.gov/7730619/). This additional nucleotide effectively "masks" the gemcitabine analog from the 3'-5' exonuclease proofreading activity of DNA polymerase, preventing its excision and repair (Miniotti et al., 2021, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8147114/). The resulting structural distortion in the DNA helix leads to the accumulation of DNA strand breaks and the activation of DNA damage response pathways. Ultimately, this process triggers cell cycle arrest in the S-phase and induces programmed cell death (apoptosis) in rapidly dividing malignant cells. This mechanism underpins the clinical utility of gemcitabine in treating various solid tumors, including pancreatic, lung, and bladder cancers.

Other names

Gemcitabine-incorporated DNAdFdCTP-DNAGemcitabine-substituted DNADNA – gemcitabine triphosphate

Masked chain termination