Precision medicine for colorectal cancer
Debmalya Barh in Precision Medicine in Cancers and Non-Communicable Diseases, 2018
Some of the patients (10%–30%) using these regimens have grade 3 toxicity such as diarrhea, nausea, mucositis/stomatitis myelosuppression, hand-foot syndrome, and occasionally cardiac toxicity. Along with this, FU leads to 0.5%–1.0% mortality (grade 5). Therefore, it is important to identify biomarkers that predict 5-FU toxicity (Rosmarin et al., 2014). 5-FU metabolism comprises a plurality of enzyme reactions. After the use of parenteral 5-FU, 70%–90% of the drug is metabolized with dihydropyrimidine dehydrogenase (DPD). The dihydropyrimidine dehydrogenase DPD, which plays a key role in the metabolism of the fluoropyrimidines, is encoded by the DPYD gene. DPD is the rate-controlling enzyme for inactivation of 5-FU and more than 80% of 5-FU is metabolized by DPD in the liver to the inactive metabolite 5,6-dihydro-5-fluorouracil (van Staveren et al., 2013).
Cancer genomics in clinics
Shirley Sun in Socio-economics of Personalized Medicine in Asia, 2016
Patients with dihydropyrimidine dehydrogenase (DPD) deficiency are more likely to have severe side effects from the chemotherapy drug 5-fluorouracil (5-FU). According to Dr. Teo, if DPD deficiency testing cannot be done, doctors may be compelled to use ethnicity as a factor to guide the dosing of 5-FU: [Administering] 5FU … I am a little bit more nervous with Malay and Indian patients. Because the DPD deficiency test is not currently available routinely. It is only available in laboratory setting, in a very sophisticated lab, and we can’t do that routinely. So what we do is that when we see patients from Malay or Indian origins, I may reduce the dose a little bit by 10 percent. But that’s based on intuition. It’s not based on science. It’s not based on protocol. It’s not based on any algorithm. It’s just based on intuition, cause that’s all I have available today. But there are no drugs that you can say “Oh Indian, take this drug. Chinese, take this drug. Malay, take this drug.” There isn’t anything like that. There isn’t.
Dihydropyrimidine Dehydrogenase Deficiency and Fluoropyrimidine-Toxicity
Sherry X. Yang, Janet E. Dancey in Handbook of Therapeutic Biomarkers in Cancer, 2021
However, therapeutic success is often limited by acute drug-adverse events, observed in up to 10–26% of the patients treated with fluoropyrimidine-based regimes [1, 2]. Frequently, these severe toxicities result in interruption of the chemotherapy and imply the risk of disease progression. Both 5FU and its oral prodrug capecitabine need to undergo enzymatic activation to fluoropyrimidine nucleotides to exert its cytotoxic effect. However, drug disposition and the efficacy/toxicity balance of 5FU are highly influenced by the action of dihydropyrimidine dehydrogenase (DPD) which constitutes the initial and rate-limiting step in the degradation of pyrimidines and fluoropyrimidines. As such, high intratumoral DPD concentrations have been associated with low efficacy of a 5FU therapy. Furthermore, low tumoral DPD levels together with low thymidine phosphorylase (TP) and thymidylate synthase (TS) expression have been associated with a favorable treatment response [5, 6]. Since more than 80% of administered 5FU is rapidly degraded by liver DPD, a general deficiency of this enzyme results in markedly prolonged exposure of the drug [7–9]. The main toxic reactions caused by reduced clearance of 5FU are myelosuppression, mucositis, diarrhea, and neuropathy including also life-threatening events. Studies investigating the DPD status suggest that reduced DPD function may account for around 50% of the toxicity cases observed under 5FU therapy [10, 11]. In addition to DPD, variations in downstream acting enzymes of the pyrimidine catabolism such as dihydropyrimidase (DPYS) and beta-ureidopropionase (UPB1) may also contribute to some extent to an altered capacity to catabolize 5FU [12–15].
Genomic medicine in Africa: a need for molecular genetics and pharmacogenomics experts
Published in Current Medical Research and Opinion, 2023
Oluwafemi G. Oluwole, Marc Henry
Genetics is driving clinical research and modern medicine globally. Genetic discoveries make it easy to evaluate individual variability to genes, environment, and lifestyle8,9. The ability to prioritize numerous disease-causing mutations has important ramifications for genomic medicine10. To date, more than 4000 diseases have been linked to mutations in genes11. Having genomic information about people is advantageous for diagnosis, prediction, and pharmacogenomics12. New genetic variants and loci with important biological functions like DNA repair, metabolism and viral immunity are being uncovered from the African datasets that need to be considered in pharmacogenomic research13. Sometimes, the function of one gene may affect other genes. The reason we performed the gene enrichment network analyses, was to identify closely related genes that may co-interact in the annotated drugs. Indeed, we identified that the DPYD gene has the highest clinically relevant variants with pharmacogenomics implications. The DPYD gene provides instructions for making an enzyme called dihydropyrimidine dehydrogenase, which is involved in the breakdown of molecules called uracil and thymine. The gene is described to influence cancer drug treatments and often co-interact with other functional genes.
Influence of a dosing-time on toxicities induced by docetaxel, cisplatin and 5-fluorouracil in patients with oral squamous cell carcinoma; a cross-over pilot study
Published in Chronobiology International, 2018
Yoshiyuki Tsuchiya, Kentaro Ushijima, Tadahide Noguchi, Naruo Okada, Jun-ichi Hayasaka, Yoshinori Jinbu, Hitoshi Ando, Yoshiyuki Mori, Mikio Kusama, Akio Fujimura
Dihydropyrimidine dehydrogenase (DPD) is a principal enzyme of degrading 5-fluorouracil. The activity of DPD exhibits a daily rhythm with higher during the resting period both in the rat liver and human peripheral blood mononuclear cells (Harris et al. 1988, 1990). It is also reported that plasma 5-fluorouracil concentration during the continuous infusion has the daily change with an anti-phase to the DPD activity (Harris et al. 1990). In addition, several clinical trials demonstrated that chronotherapy of 5-fluorouracil adapting the drug delivery to the daily rhythm of DPD enzyme activity were less toxic (Falcone et al. 1999; Lévi et al. 1997). Therefore, DCF chemotherapy with chronomodulate-infusion of 5-fluorouracil and evening-dosing of docetaxel and cisplatin seems to be more effective for diminishing the chemotherapy-induced toxicities such as neutropenia and diarrhea.
Capecitabine-associated enterocolitis: Narrative literature review of a rare adverse event and a case presentation
Published in Journal of Chemotherapy, 2023
Ioannis P. Trontzas, Vasiliki E. Rapti, Nikolaos K. Syrigos, Georgia Gomatou, Styliani Lagou, George Kanellis, Elias A. Kotteas
Capecitabine is a 5-fluorouracil (FU) oral prodrug with antimetabolite activity against a variety of tumours. Development of this oral prodrug targeted to the establishment of a better tolerability/safety profile compared to previous more toxic 5-FU based regimens, such as standard 5-FU/leucovorin Mayo Clinic regimen [1]. This is achieved through the metabolic conversion of capecitabine to 5-FU through the enzymatic activity of thymidine phosphorylase (ThyPase), which allows activation of FU selectively in tumour tissues and in less extent in the adjacent healthy tissues with consequent low systemic toxicity (Figure 1) [1,2]. Dihydropyrimidine dehydrogenase (DPD) plays an important role in the catabolism of 5-FU as a rate-limiting enzyme. Deficiency of the DPYD gene encoding for DPD synthesis may lead to potentially life-threatening capecitabine toxicity [3]. 5-FU exerts its cytotoxic effects as an antimetabolite agent primarily through the depletion of thymidine following the binding of 5-FU with the enzyme thymidylate synthase (TS) which allows for TS inhibition [4].
Related Knowledge Centers
- Catalysis
- Chemical Reaction
- Dihydrouracil
- Enzyme
- Nicotinamide Adenine Dinucleotide Phosphate
- Thymine
- Uracil
- Substrate
- Product
- Gene