difluorodeoxycytidine

Difluorodeoxycytidine, also known as gemcitabine, is a nucleoside analog used as a chemotherapy agent. It is the 2',2'-difluoro-2'-deoxycytidine, a cytidine analog in which the 2' position of the sugar is difluorinated. In cells, gemcitabine is phosphorylated by deoxycytidine kinase to dFdCMP, then further to dFdCDP and dFdCTP, the latter two active metabolites.

Mechanism of action involves two pathways. DFdCTP competes with dCTP for incorporation into DNA by DNA polymerases and acts as a chain terminator after incorporation. DFdCDP inhibits ribonucleotide reductase, lowering the pool of deoxynucleotides available for DNA synthesis and repair, which enhances cytotoxicity. The combination of DNA synthesis inhibition and depletion of nucleotide pools underlies its antitumor activity.

Pharmacokinetics and administration: gemcitabine is given intravenously. It has a short plasma half-life due to rapid deamination by cytidine deaminase to difluorodeoxyuridine (dFdU) and is primarily renally excreted. Dose and schedule are adjusted based on organ function, particularly renal function, and treatment is guided by clinical context and prior therapies.

Clinical use: gemcitabine is approved for several solid tumors, most notably pancreatic cancer, where it is commonly used as monotherapy or in combination regimens (for example with nab-paclitaxel), and it is also used in non-small cell lung cancer and bladder cancer, among others. It is employed in various regimens and lines of therapy depending on the tumor type and regional approvals.

Adverse effects and precautions: common toxicities include myelosuppression (neutropenia, thrombocytopenia), nausea, vomiting, mucositis, rash, and elevated liver enzymes. Renal impairment may necessitate dose adjustments; monitoring of blood counts and organ function is standard. It should be used with caution in pregnancy.