5-Fluorouracil (5-FU) resistance pathways (5-FU resistance)

5-Fluorouracil (5-FU) resistance pathways represent the multifaceted biological mechanisms that cancer cells utilize to evade the cytotoxic effects of 5-FU, a widely used antimetabolite (Longley et al., 2003 [1]). The primary mechanism involves the upregulation of thymidylate synthase (TYMS), the enzyme 5-FU is designed to inhibit, thereby maintaining dTMP production for DNA synthesis (Peters et al., 2002 [2]). Additionally, high levels of dihydropyrimidine dehydrogenase (DPYD) can lead to rapid catabolism of the drug, reducing its bioavailability and therapeutic impact (Diasio and Johnson, 1999 [3]). Resistance is also linked to deficiencies in activating enzymes such as orotate phosphoribosyltransferase (OPRT) and thymidine phosphorylase (TYMP), which are necessary to convert 5-FU into its active metabolites (Ichikawa et al., 2003 [4]). Furthermore, alterations in apoptotic signaling, such as p53 mutations or overexpression of anti-apoptotic proteins like Bcl-2, allow cells to survive 5-FU-induced DNA damage (Zhang et al., 2008 [5]). Changes in drug transport, specifically the overexpression of multidrug resistance-associated proteins (MRPs), can further decrease intracellular drug concentration (Longley et al., 2003 [1]). Understanding these pathways is vital for developing combination therapies and personalized treatment strategies to overcome chemoresistance in various malignancies, particularly colorectal cancer. References: [1] Longley DB, et al. 5-Fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer. 2003;3(5):330-8. [2] Peters GJ, et al. Thymidylate synthase and drug resistance. Eur J Cancer. 2002;38(6):758-66. [3] Diasio RB, Johnson MR. Dihydropyrimidine dehydrogenase: its role in 5-fluorouracil clinical toxicity and tumor resistance. Clin Cancer Res. 1999;5(10):2672-3. [4] Ichikawa W, et al. Both gene expression of thymidylate synthase and orotate phosphoribosyltransferase predict response to 5-fluorouracil. Clin Cancer Res. 2003;9(11):4059-64. [5] Zhang N, et al. 5-Fluorouracil: mechanisms of resistance and reversal strategies. Molecules. 2008;13(8):1551-69.

Other names

5-FU chemoresistanceFluorouracil resistance mechanismsResistance to 5-fluorouracil

Inhibition of thymidylate synthase and incorporation of fluoronucleotides into RNA and DNA, leading to cell cycle arrest and apoptosis; resistance mechanisms counteract these effects through enzyme upregulation or altered metabolism (Longley et al., 2003 [1]).