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Review
. 2022 Oct 6;5(11):1017-1033.
doi: 10.1021/acsptsci.2c00117. eCollection 2022 Nov 11.

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

Himanshu Verma  1 , Gera Narendra  1 , Baddipadige Raju  1 , Pankaj Kumar Singh  2 , Om Silakari  1
Affiliations
Review

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

Himanshu Verma et al. ACS Pharmacol Transl Sci. .

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.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Mechanism of the action of 5-FU as an anticancer drug.
Figure 2
Figure 2
Mechanism of 5-FU inactivation via DPD.
Figure 3
Figure 3
Network analysis of miRNAs associated with DPYD gene expression.
Figure 4
Figure 4
(A) 2D interaction diagram; (B) 3D electrostatic complementarity map for a complex of DPD–5-FU.
Figure 5
Figure 5
5-FU/prodrugs and DPD inhibitors designed and evaluated to counter DPD-mediated 5-FU resistance.
Figure 6
Figure 6
DPD-downregulators and formulation developed to counter DPD-mediated 5-FU resistance.
Figure 7
Figure 7
(A). Capecitabine biotransformation to 5-FU and its subsequent inactivation via DPD. (B) RO0094889 activation to 5-VU, an active metabolite and DPD inhibitor.
Figure 8
Figure 8
NUC-3373, a pyrimidine nucleotide analogue that can bypass DPD-mediated inactivation.
Figure 9
Figure 9
Novel prodrug of 5-FU (compound 4) in a lactim-type structure.
Figure 10
Figure 10
Novel prodrug of 5-FU in a lactim-type structure.
Figure 11
Figure 11
SAR of pyrrolidine–pyrazole-based derivatives as S1PR2 inhibitors to potently reverse 5-FU resistance by downregulating DPD expression in colorectal cancer.
Figure 12
Figure 12
New JTE-013 derivative as S1PR2 inhibitors.
Figure 13
Figure 13
SLR080811; SphK2 selective inhibitor.
Figure 14
Figure 14
Reported DPD inhibitors.
Figure 15
Figure 15
Formulations developed to enhance the 5-FU bioavailability.
Figure 16
Figure 16
Exosomes to codeliver miR-21 inhibitor and 5-FU.
See this image and copyright information in PMC

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