A molecular modeling study of the interaction of 2′-fluoro-substituted analogues of dUMP/FdUMP with thymidylate synthase

Jarmuła, Adam; Dowiercial, A.; Rode, Wojciech

doi:10.1016/j.bmcl.2008.03.016

Cited by 4 publications

(3 citation statements)

References 33 publications

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“…Reduction of dTMP leads to downstream depletion of deoxythymidine triphosphate (dTTP), which induces perturbations in the levels of the other deoxynucleotides (dATP, dGTP and dCTP). Finally the imbalances (the ATP/dTTP ratio specifically) are thought to severely disrupt DNA synthesis and repair, resulting in lethal DNA damage [ 17 , 18 ]. Accumulation of dUMP, which might subsequently lead to increased levels of deoxyuri-dine triphosphate (dUTP), can be misincorporated into DNA, and FdUTP, the metabolic product of 5-FU has the same action [ 19 ].…”

Section: Mechanism Of Actionmentioning

confidence: 99%

5-Fluorouracil: Mechanisms of Resistance and Reversal Strategies

et al. 2008

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The purpose of this work is to review the published studies on the mechanisms of action and resistance of 5-fluorouracil. The review is divided into three main sections: mechanisms of anti-tumor action, studies of the resistance to the drug, and procedures for the identification of new genes involved in resistance with microarray techniques. The details of the induction and reversal of the drug resistance are also described.

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Section: Mechanism Of Actionmentioning

confidence: 99%

5-Fluorouracil: Mechanisms of Resistance and Reversal Strategies

et al. 2008

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“…This interaction inhibits the production of deoxythymidine monophosphate (dTMP), which is a crucial precursor for DNA replication and repair [ 20 ]. The depletion of dTMP leads to an imbalance in intracellular nucleotides, ultimately resulting in double-stranded DNA breaks mediated by endonuclease activity [ 21 ]. Furthermore, 5-fluorouracil is a pyrimidine analogue that misincorporates into RNA and DNA, substituting for uracil or thymine [ 22 ].…”

Section: Discussionmentioning

confidence: 99%

Atypical Fibroxanthoma Treated with a Topical Combination of Imiquimod, Tazarotene, and 5-Fluorouracil

Nahm,

Badiavas,

Kirsner

et al. 2024

Dermatol Ther (Heidelb)

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This case report describes an 80-year-old man who presented with a growing erythematous nodule with erosion, measuring 0.6 cm × 0.6 cm, on his right temple. This lesion was later diagnosed as atypical fibroxanthoma (AFX). Instead of undergoing Mohs surgery, the gold standard treatment, the patient opted to pursue a topical treatment regimen because of financial costs associated with surgical removal and repair. This topical regimen consisted of tazarotene cream, imiquimod cream, and 5-fluorouracil solution, applied for 30 days. The patient was directed to use this combination 5 days per week for 6 weeks. The specified dosage for each medication was a fifth of a packet of imiquimod 5% cream, an equivalent amount of tazarotene 0.1% cream, and a single drop of 5-fluorouracil 2% solution. These were combined on a bandage and placed on the lesion overnight. Following the treatment, a 3-week post-application examination revealed an erosion, 1.0 cm × 0.9 cm, amidst erythema. A subsequent incisional biopsy with histopathology and stains for CD10 and CD99, 3 weeks after treatment, and three punch biopsies with histopathology and stains for CD10 and CD99, 1-year post-treatment, confirmed the absence of AFX. AFX is a superficial variant of pleomorphic dermal sarcoma (PDS), which shares histologic similarities, yet the exact relationship between AFX/PDS and undifferentiated pleomorphic sarcoma is still not well understood. Previous studies have indicated a genomic similarity between AFX/PDS and cutaneous squamous cell carcinoma (cSCC), which suggests the potential efficacy of cSCC-targeted treatments for AFX/PDS. This case marks the first recorded instance of successful topical medical treatment of AFX, offering an alternative for patients who may opt out of surgical intervention. Continued research to assess the broader efficacy of this approach is encouraged.

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“…As known, 5-FU has a much more complicated manner in terms of the mechanism of actions to induce cell death 43 . It has also been reported that the imbalances of deoxynucleotides would severely disrupt DNA synthesis and repair, resulting in lethal DNA damage and causing cell death 44 . This may explain why under 5-FU treatment, the supplement of dA, dG, and dC lead to more cell death due to the imbalanced pools of deoxynucleotides, while future research remains to be done.…”

Section: Discussionmentioning

confidence: 99%

Targeting keratin 17-mediated reprogramming of de novo pyrimidine biosynthesis to overcome chemoresistance in pancreatic cancer

Pan

Chaika

Tseng

et al. 2022

Preprint

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Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer death. We previously reported keratin 17 (K17) as a novel negative prognostic and predictive biomarker, whose overexpression confers the resistance to chemotherapies. Here, we investigated the mechanisms of chemoresistance and tumor-specific vulnerabilities that can be exploited for targeted therapies for K17-expressing PDAC. Unbiased metabolomic studies in isogenic PDAC models identified several key metabolic pathways that are upregulated in the presence of K17. We demonstrate that K17 increases pyrimidine biosynthesis, a pathway that has been linked to chemoresistance. Patient dataset analysis revealed that K17 expression and enzymes involved in pyrimidine, but not purine, de novo biosynthesis is associated with shorter patient survival. Rescue experiments showed that deoxycytidine (dC) and deoxythymidine (dT) were sufficient to promote resistance to Gemcitabine (a dC analog) and 5-fluorouracil (a dT analog), respectively. Furthermore, K17-expressing cells were more sensitive to Brequinar, a specific inhibitor of dihydroorotate dehydrogenase (DHODH), the rate-limiting enzyme in de novo pyrimidine biosynthetic pathway. Targeting DHODH by small interfering RNA or by Brequinar with Gemcitabine synergistically inhibited the viability of K17-positive PDAC cells. Importantly, the combination of Gemcitabine and Brequinar significantly inhibited the growth of K17-expressing tumors and extended survival of mice bearing K17-expressing PDACs. Overall, we identified a novel pathway of chemoresistance and a metabolic target of which could lead to the development of a biomarker-based therapy for K17-expressing PDAC.

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A molecular modeling study of the interaction of 2′-fluoro-substituted analogues of dUMP/FdUMP with thymidylate synthase

Cited by 4 publications

References 33 publications

5-Fluorouracil: Mechanisms of Resistance and Reversal Strategies

5-Fluorouracil: Mechanisms of Resistance and Reversal Strategies

Atypical Fibroxanthoma Treated with a Topical Combination of Imiquimod, Tazarotene, and 5-Fluorouracil

Targeting keratin 17-mediated reprogramming of de novo pyrimidine biosynthesis to overcome chemoresistance in pancreatic cancer

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