Perturbing the Movement of Hydrogens to Delineate and Assign Events in the Reductive Activation and Turnover of Porcine Dihydropyrimidine Dehydrogenase

Biochemistry ◽  
2021 ◽  
Author(s):  
Brett A. Beaupre ◽  
Dariush C. Forouzesh ◽  
Arseniy Butrin ◽  
Dali Liu ◽  
Graham R. Moran
Keyword(s):  
Dihydropyrimidine Dehydrogenase ◽  
Reductive Activation

Transient-State Analysis of Porcine Dihydropyrimidine Dehydrogenase Reveals Reductive Activation by NADPH

Biochemistry ◽  
2020 ◽  
Vol 59 (26) ◽  
pp. 2419-2431
Author(s):  
Brett A. Beaupre ◽  
Dariush C. Forouzesh ◽  
Graham R. Moran
Keyword(s):  
Dihydropyrimidine Dehydrogenase ◽  
Transient State ◽  
Reductive Activation ◽  
State Analysis

scholarly journals Epithelial-Mesenchymal Transition and MicroRNAs in Colorectal Cancer Chemoresistance to FOLFOX

Pharmaceutics ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 75
Author(s):  
Paula I. Escalante ◽  
Luis A. Quiñones ◽  
Héctor R. Contreras
Keyword(s):  
Colorectal Cancer ◽  
Tumor Cells ◽  
Methylenetetrahydrofolate Reductase ◽  
Epithelial Mesenchymal Transition ◽  
Late Onset ◽  
Dihydropyrimidine Dehydrogenase ◽  
Acquired Resistance ◽  
Potential Effect ◽  
Mesenchymal Transition ◽  
Folfox Chemotherapy

The FOLFOX scheme, based on the association of 5-fluorouracil and oxaliplatin, is the most frequently indicated chemotherapy scheme for patients diagnosed with metastatic colorectal cancer. Nevertheless, development of chemoresistance is one of the major challenges associated with this disease. It has been reported that epithelial-mesenchymal transition (EMT) is implicated in microRNA-driven modulation of tumor cells response to 5-fluorouracil and oxaliplatin. Moreover, from pharmacogenomic research, it is known that overexpression of genes encoding dihydropyrimidine dehydrogenase (DPYD), thymidylate synthase (TYMS), methylenetetrahydrofolate reductase (MTHFR), the DNA repair enzymes ERCC1, ERCC2, and XRCC1, and the phase 2 enzyme GSTP1 impair the response to FOLFOX. It has been observed that EMT is associated with overexpression of DPYD, TYMS, ERCC1, and GSTP1. In this review, we investigated the role of miRNAs as EMT promotors in tumor cells, and its potential effect on the upregulation of DPYD, TYMS, MTHFR, ERCC1, ERCC2, XRCC1, and GSTP1 expression, which would lead to resistance of CRC tumor cells to 5-fluorouracil and oxaliplatin. This constitutes a potential mechanism of epigenetic regulation involved in late-onset of acquired resistance in mCRC patients under FOLFOX chemotherapy. Expression of these biomarker microRNAs could serve as tools for personalized medicine, and as potential therapeutic targets in the future.

scholarly journals Inactivation of dihydropyrimidine dehydrogenase by 5-iodouracil.

1991 ◽  
Vol 266 (30) ◽  
pp. 19988-19994
Author(s):  
D.J. Porter ◽  
W.G. Chestnut ◽  
L.C. Taylor ◽  
B.M. Merrill ◽  
T. Spector
Keyword(s):  
Dihydropyrimidine Dehydrogenase

scholarly journals Alternative chemoradiotherapy in anal carcinoma patients with mutations in thymidylate synthase and dihydropyrimidine dehydrogenase genes

2021 ◽  
Vol 14 ◽  
pp. 175628482110244
Author(s):  
Muhammad Wasif M. Saif ◽  
Ruchi Hamal ◽  
Nauman Siddiqui ◽  
Antonia Maloney ◽  
Melissa Smith
Keyword(s):  
Dihydropyrimidine Dehydrogenase ◽  
Anal Carcinoma ◽  
Complete Response ◽  
Genetic Mutations ◽  
Molecular Testing ◽  
Severe Toxicity ◽  
Metabolizing Enzymes ◽  
Radiological Response ◽  
A Prospective Study ◽  
To Receive

Background: 5-fluorouracil (5-FU) and mitomycin-C (MMC) with radiotherapy (RT) remain an established treatment for patients with anal cancer (AC). Genetic mutations in two major metabolizing enzymes for 5-FU; dihydropyrimidine dehydrogenase ( DPYD and thymidylate synthetase ( TYMS), have been associated with clinical response and toxicity. However, their place in the treatment of AC remains undetermined. Methods: We retrospectively reviewed 21 patients with AC, including T2-4, N0-1, M0 or T1-4, N2-3, and M0 treated between 2012 and 2018. All patients were treated with 5-FU 1,000 mg/m2/day via continuous intravenous (IV) infusion 1–4 and 29–32, MMC 10 mg/m2 IV bolus days 1 and 29 plus RT. Patients who developed ⩾3 grade toxicities were tested for the DPYD and TYMS genes. Treatment was either modified with reduced doses or changed to MMC 10 mg/m2 day 1 and 29 with cisplatin 25 mg/m2/week plus RT. Toxicities and responses were collected. Results: Six out of 21 patients who developed ⩾3 grade toxicities including pancytopenia, neutropenia, thrombocytopenia, mucositis, nausea, rash, and nephritis were found to have genetic mutations: TYMS 2RG/3RC ( n = 2), 3RG/3RC ( n = 1), 2R/2R ( n = 2), T YMS 3′UTR del/Ins ( n = 2), and DPYD c.2864A > T heterozygous ( n = 1). Two patients received 5-FU at a 50% reduced dose on days 29–32; one patient refused to receive 5-FU (continued with MMC and RT); one patient received only radiation therapy due to persistent pancytopenia despite the use of growth factors; two patients received an alternative regimen consisting of MMC 10 mg/m2 on day 29 with cisplatin (CDDP) 25 mg/m2/week plus RT; and two patients received cisplatin/MMC with RT from the beginning as they were prospectively detected to have TYMS abnormalities prior to dosing the chemotherapy. These patients tolerated treatment very well with only grade 2 toxicities. All the patients (4/4) on cisplatin/MMC achieved clinical complete response (cCR), while four patients (4/15) on 5-FU/MMC reached cCR at the first assessment. Radiological response showed complete response at the end of 24 weeks assessment. Conclusions: Molecular testing for DPYD and TYMS genes can allow us to identify patients who are most likely to respond or face severe toxicity to 5-FU in a potentially curable cancer. Combining radiation with CDDP with MMC in patients with AC is feasible. A prospective study based on pharmacogenetic testing comparing MMC/cisplatin with MMC/5-FU is indicated in patients with AC.

scholarly journals The Role of Superoxide and Hydroperoxide in the Reductive Activation of Tryptophan-2,3-dioxygenase

1971 ◽  
Vol 246 (23) ◽  
pp. 7119-7124
Author(s):  
Frank O. Brady ◽  
Henry Jay Forman ◽  
Philip Feigelson
Keyword(s):  
Reductive Activation
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