Chemistry of Fluorinated Pyrimidines in the Era of Personalized Medicine

Gmeiner, William H.

doi:10.3390/molecules25153438

Cited by 22 publications

(14 citation statements)

References 94 publications

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“…Deficiencies in MMR occur either as the result of germ-line mutation conferring increased risk for colon cancer (e.g., Lynch syndrome; ~15%), or from epigenetic silencing of MMR genes (~85%). The mechanistic basis for lack of efficacy of FPs in dMMR CRC is not clearly understood, however MSI is also associated with elevated thymidylate synthase (TS) ( 20 , 21 ), which is the molecular target of FP chemotherapy ( 2 ).…”

Section: Methodsmentioning

confidence: 99%

A narrative review of genetic factors affecting fluoropyrimidine toxicity

Gmeiner¹

2021

Precis Cancer Med

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Objective: Our objective is to document progress in developing personalized therapy with fluoropyrimidine drugs (FPs) to improve outcomes for cancer patients and to identify areas requiring further investigation. Background: FPs including 5-fluorouracil (5-FU), are among the most widely used drugs for treating colorectal cancer (CRC) and other gastrointestinal (GI) malignancies. While FPs confer a survival benefit for CRC patients, serious systemic toxicities, including neutropenia, occur in ~30% of patients with lethality in 0.5–1% of patients. While serious systemic toxicities may occur in any patient, patients with polymorphisms in DPYD , which encodes the rate-limiting enzyme for pyrimidine degradation are at very high risk. Other genetic factors affecting risk for 5-FU toxicity, including miR-27a, are under investigation. Methods: Literature used to inform the text of this article was selected from PubMed.gov from the National Library of Medicine while regulatory documents were identified via Google search. Conclusions: Clinical studies to date have validated four DPYD polymorphisms ( DPYD *2A, DPYD *13, c.2846A>T, HapB3) associated with serious toxicities in patients treated with 5-FU. Genetic screening for these is being implemented in the Netherlands and the UK and has been shown to be a cost-effective way to improve outcomes. Factors other than DPYD polymorphisms (e.g., miR-27a, TYMS , ENOSF1, p53) also affect 5-FU toxicity. Functional testing for deficient pyrimidine catabolism {defined as [U] >16 ng/mL or [UH2]:[U] <10} is being implemented in France and has demonstrated utility in identifying patients with elevated risk for 5-FU toxicity. Therapeutic drug monitoring (TDM) from plasma levels of 5-FU during first cycle treatment also is being used to improve outcomes and pharmacokinetic-based dosing is being used to increase the percent of patients within optimal area under the curve (AUC) (18–28 mg*h/L) values. Patients maintained in the optimal AUC range experienced significantly reduced systemic toxicities. As understanding the genetic basis for increased risk of 5-FU toxicity becomes more refined, the development of functional-based methods to optimize treatment is likely to become more widespread.

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Section: Methodsmentioning

confidence: 99%

A narrative review of genetic factors affecting fluoropyrimidine toxicity

Gmeiner¹

2021

Precis Cancer Med

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“…Therefore, successful direct delivery of 5FUTPs could skip several activation steps and may overcome 5FU resistance in PDAC. 45 Here, we show that 5FU-EGFR aptamers specifically internalized in EGFR-expressing cells via receptormediated clathrin-dependent endocytosis escape from lysosomes in a biphasic manner and thus evade 5FU resistance-associated efflux. Additionally, the cytoplasmic release of 5FUTP increases the potency of 5FU-EGFR aptamers in 5FU-refractory cells.…”

Section: Discussionmentioning

confidence: 71%

Tumor-Specific Delivery of 5-Fluorouracil–Incorporated Epidermal Growth Factor Receptor–Targeted Aptamers as an Efficient Treatment in Pancreatic Ductal Adenocarcinoma Models

Mahajan

Alnatsha

et al. 2021

Gastroenterology

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“…There are many defects of 5-FU, including systemic toxicities because of non-specific cytotoxicity for tumor cell, loss of efficiency due to poor distribution to tumor sites, and severely limited efficacy because of drug resistance ( Alvarez et al, 2012 ). The serious systemic toxicities of 5-FU are commonly seen in gastrointestinal and hematopoietic effects ( Gmeiner, 2020 ).…”

Section: Resistance In Fluorinated Pyrimidinesmentioning

confidence: 99%

Mechanisms of Pharmaceutical Therapy and Drug Resistance in Esophageal Cancer

Mao

Zeng

Zhang

et al. 2021

Front. Cell Dev. Biol.

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Pharmaceutical therapies are essential for esophageal cancer (EC). For the advanced EC, the neoadjuvant therapy regimen, including chemotherapy plus radiotherapy and/or immunotherapy, is effective to achieve clinical benefit, even pathological complete response. For the unresectable, recurrent, and metastatic EC, the pharmaceutical therapy is the limited effective regimen to alleviate the disease and prolong the progression-free survival and overall survival. In this review, we focus on the pharmaceutical applications in EC treatment including cytotoxic agents, molecular targeted antibodies, and immune checkpoint inhibitors (ICIs). The chemotherapy regimen is based on cytotoxic agents such as platinum-based complexes, fluorinated pyrimidines and taxenes. Although the cytotoxic agents have been developed in past decades, the standard chemotherapy regimen is still the cisplatin and 5-FU or paclitaxel because the derived drugs have no significant advantages of overcoming the shortcomings of side effects and drug resistance. The targeted molecular therapy is an essential supplement for chemotherapy; however, there are only a few targeted therapies available in clinical practice. Trastuzumab and ramucirumab are the only two molecular therapy drugs which are approved by the US Food and Drug Administration to treat advanced and/or metastatic EC. Although the targeted therapy usually achieves effective benefits in the early stage therapy of EC, the patients will always develop drug resistance during treatment. ICIs have had a significant impact on routine clinical practice in cancer treatment. The anti-programmed cell death-1 monoclonal antibodies pembrolizumab and nivolumab, as the ICIs, are recommended for advanced EC by several clinical trials. However, the significant issues of pharmaceutical treatment are still the dose-limiting side effects and primary or secondary drug resistance. These defects of pharmaceutical therapy restrain the clinical application and diminish the effectiveness of treatment.

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Chemistry of Fluorinated Pyrimidines in the Era of Personalized Medicine

Cited by 22 publications

References 94 publications

A narrative review of genetic factors affecting fluoropyrimidine toxicity

A narrative review of genetic factors affecting fluoropyrimidine toxicity

Tumor-Specific Delivery of 5-Fluorouracil–Incorporated Epidermal Growth Factor Receptor–Targeted Aptamers as an Efficient Treatment in Pancreatic Ductal Adenocarcinoma Models

Mechanisms of Pharmaceutical Therapy and Drug Resistance in Esophageal Cancer

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