Dataset Information

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.

SUBMITTER: Verma H

PROVIDER: S-EPMC9667542 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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

Verma Himanshu H Narendra Gera G Raju Baddipadige B Singh Pankaj Kumar PK Silakari Om O

ACS pharmacology & translational science 20221006 11

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 ...[more]

PMID: 36407958

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Project description:BackgroundThe main cause for fluoropyrimidine-related toxicity is deficiency of the metabolizing enzyme dihydropyrimidine dehydrogenase (DPD). In 2020, the European Medicines Agency (EMA) recommended two methods for pre-treatment DPD deficiency testing in clinical practice: phenotyping using endogenous uracil concentration or genotyping for DPYD risk variant alleles. This study assessed the DPD testing implementation status in Europe before (2019) and after (2021) the release of the EMA recommendations.MethodsThe survey was conducted from 16 March 2022 to 31 July 2022. An electronic form with seven closed and three open questions was e-mailed to 251 professionals with DPD testing expertise of 34 European countries. A descriptive analysis was conducted.ResultsWe received 79 responses (31%) from 23 countries. Following publication of the EMA recommendations, 87% and 75% of the countries reported an increase in the amount of genotype and phenotype testing, respectively. Implementation of novel local guidelines was reported by 21 responders (27%). Countries reporting reimbursement of both tests increased in 2021, and only four (18%) countries reported no coverage for any testing type. In 2019, major implementation drivers were 'retrospective assessment of fluoropyrimidine-related toxicity' (39%), and in 2021, testing was driven by 'publication of guidelines' (40%). Although the major hurdles remained the same after EMA recommendations-'lack of reimbursement' (26%; 2019 versus 15%; 2021) and 'lack of recognizing the clinical relevance by medical oncologists' (25%; 2019 versus 8%; 2021)-the percentage of specialists citing these decreased. Following EMA recommendations, 25% of responders reported no hurdles at all in the adoption of the new testing practice in the clinics.ConclusionsThe EMA recommendations have supported the implementation of DPD deficiency testing in Europe. Key factors for successful implementation were test reimbursement and clear clinical guidelines. Further efforts to improve the oncologists' awareness of the clinical relevance of DPD testing in clinical practice are needed.

Dataset Information

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

Publications

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

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