Dihydropyrimidine Dehydrogenase-Mediated Resistance to 5-Fluorouracil: Mechanistic Investigation and Solution

Abstract

5-Fluorouracil (5-FU) is one of the most widely used chemotherapeutics for the treatment of cancers associated with the aerodigestive tract, breast, and colorectal system. The efficacy of 5-FU is majorly affected by dihydropyrimidine dehydrogenase (DPD) as it degrades more than 80% of administered 5-FU into an inactive metabolite, dihydrofluorouracil. Herein we discuss the molecular mechanism of this inactivation by analyzing the interaction pattern and electrostatic complementarity of the DPD–5-FU complex. The basis of DPD overexpression in cancer cell lines due to significantly distinct levels of the miRNAs (miR-134, miR-27b, and miR-27a) compared to normal cells has also been outlined. Additionally, some kinases including sphingosine kinase 2 (SphK2) have been reported to correlate with DPD expression. Currently, to address this problem various strategies are reported in the literature, including 5-FU analogues (bypass the DPD-mediated inactivation), DPD downregulators (regulate the DPD expression levels in tumors), inhibitors (as promising adjuvants), and formulation development loaded with 5-FU (liposomes, nanoparticles, nanogels, etc.), which are briefly discussed in this Review.

Advanced prodrug strategies in nucleoside analogues targeting the treatment of gastrointestinal malignancies

“…5-FU is an essential nucleobase which has been frequently administered to GI cancer patients since 1957 ( Verma et al, 2022 ) ( Table 1 ). Bearing a fluorine atom at position 5 of uracil, 5-FU is catalyzed by the corresponding enzyme as active metabolites that could incorporate into RNA (5-FU-5′-triphosphate, FUTP) and DNA (2′-deoxyribose-5-FU-5′-triphosphate, FdUTP) and inhibit the nucleotide synthetic enzyme thymidylate synthase ( Longley et al, 2003 ; Sethy and Kundu, 2021 ).…”

Endogenous stimuli-responsive separating microneedles to inhibit hypertrophic scar through remodeling the pathological microenvironment

“…5-Fu, capable of inhibiting cell proliferation, inducing fibroblast apoptosis, and decreasing collagen production, has been used alone or in combination with corticosteroids to avoid the potential side effects of corticosteroid injections in clinical guideline and practice. Yet, due to the elimination by endogenous dihydropyrimidine dehydrogenase, the half-life of 5-Fu is short, which requires high injection dose and multiple operations 13 , 14 . Specifically, the high-dose local administration may induce serious side effects (e.g., vasculitis, hyperpigmentation, etythema, purpura, burning sensation), and the invasive injection is accompanied with intense pain 15 , 16 .…”