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Pathway Description
Gemcitabine Action Pathway
Homo sapiens
Drug Action Pathway
Created: 2021-05-18
Last Updated: 2023-10-25
Gemcitabine is a nucleoside metabolic inhibitor used as adjunct therapy in the treatment of certain types of ovarian cancer, non-small cell lung carcinoma, metastatic breast cancer, and as a single agent for pancreatic cancer.
As a prodrug, gemcitabine is transformed into its active metabolites that work by replacing the building blocks of nucleic acids during DNA elongation, arresting tumor growth and promoting apoptosis of malignant cells.
After uptake into malignant cells, gemcitabine is phosphorylated by deoxycytidine kinase to form gemcitabine monophosphate, which is then converted to the active compounds, gemcitabine diphosphate (dFdCDP) and gemcitabine triphosphate (dFdCTP).
dFdCTP competes with deoxycytidine triphosphate (dCTP) for incorporation into DNA, thereby competitively inhibiting DNA chain elongation. The non-terminal position of dFdCTP in the DNA chain prevents detection of dFdCTP in the chain and repair by proof-reading 3′5′-exonuclease: this process is referred to as "masked DNA chain termination." Incorporation of dFdCTP into the DNA chain ultimately leads to chain termination, DNA fragmentation, and apoptotic cell death of malignant cells.
Gemcitabine is cell cycle specific and inhibits the S phase and the progression through the G1/s phase boundary.
References
Gemcitabine Pathway References
National Center for Biotechnology Information (2021). PubChem Compound Summary for CID 60750, Gemcitabine. Retrieved September 1, 2021 from https://pubchem.ncbi.nlm.nih.gov/compound/Gemcitabine.
Alvarellos, M. L., Lamba, J., Sangkuhl, K., Thorn, C. F., Wang, L., Klein, D. J., Altman, R. B., & Klein, T. E. (2014). PharmGKB summary: gemcitabine pathway. Pharmacogenetics and genomics, 24(11), 564–574. https://doi.org/10.1097/FPC.0000000000000086
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