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Pathway Description
Capecitabine Action Pathway (New)
Homo sapiens
Drug Action Pathway
Capecitabine is a nucleoside metabolic inhibitor, orally-administered chemotherapeutic agent indicated to treat colon, colorectal and breast cancer. Capecitabine is a prodrug, that is enzymatically converted to fluorouracil (antimetabolite) in the tumor, where it inhibits DNA synthesis and slows growth of tumor tissue. Capecitabine is used for the treatment of patients with metastatic breast cancer resistant to both paclitaxel and an anthracycline-containing chemotherapy regimen. May also be used in combination with docetaxel for the treatment of metastatic breast cancer in patients who have failed to respond to, or recurred or relasped during or following anthracycline-containing chemotherapy. Capecitabine is used alone as an adjuvant therapy following the complete resection of primary tumor in patients with stage III colon cancer when monotherapy with fluroprymidine is preferred. Capecitabine is a prodrug that is selectively tumour-activated to its cytotoxic moiety, fluorouracil, by thymidine phosphorylase, an enzyme found in higher concentrations in many tumors compared to normal tissues or plasma. Fluorouracil is further metabolized to two active metabolites, 5-fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP), within normal and tumour cells. These metabolites cause cell injury by two different mechanisms. First, FdUMP and the folate cofactor, N5-10-methylenetetrahydrofolate, bind to thymidylate synthase (TS) to form a covalently bound ternary complex. This binding inhibits the formation of thymidylate from 2'-deaxyuridylate. Thymidylate is the necessary precursor of thymidine triphosphate, which is essential for the synthesis of DNA, therefore a deficiency of this compound can inhibit cell division. Secondly, nuclear transcriptional enzymes can mistakenly incorporate FUTP in place of uridine triphosphate (UTP) during the synthesis of RNA. This metabolic error can interfere with RNA processing and protein synthesis through the production of fraudulent RNA.
References
Capecitabine Pathway (New) References
Deepthi A, Raju S, Kalyani A, Udaya K. M, Vanaja A. Targeted Drug Delivery to the Nucleus and its Potential Role in Cancer Chemotherapy. J. Pharm. Sci. & Res. 5 (2): 48-56, 2013.
Higby K. J, Bischal M. M, Campbell C. A, Anderson R. G, Broskin S. A, Foltz L. E, Koper J. A, Nickle A. C, Resendes K. K. 5-Fluorouracil disrupts nuclear export and nuclear pore permeability in a calcium dependent manner. Apoptosis 22: 393-405, 2017.
Bunz F. Thymidylate synthase and 5-fluorouracil: a cautionary tale. Cancer Biology & Therapy 7 (7): 995-996, 2008.
Wishart DS, Feunang YD, Guo AC, Lo EJ, Marcu A, Grant JR, Sajed T, Johnson D, Li C, Sayeeda Z, Assempour N, Iynkkaran I, Liu Y, Maciejewski A, Gale N, Wilson A, Chin L, Cummings R, Le D, Pon A, Knox C, Wilson M: DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 2018 Jan 4;46(D1):D1074-D1082. doi: 10.1093/nar/gkx1037.
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