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Introduction to Cancer
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Currently, there is significant interest in identifying pharmacogenomic markers of both efficacy and toxicity for anticancer therapies. The availability of robust biomarkers would allow patients to be screened to assess whether a particular drug is likely to work and to predict the risk of developing serious side effects to a particular drug. One example where it is already possible to predict toxicity is with 5-fluorouracil (5-FU) (see Chapters 3 and 11). A small percentage of individuals (3–5%) are deficient in the enzyme dihydropyrimidine dehydrogenase (DPD), which is crucial for the metabolism of this agent. In these patients, due to a build-up of the drug during chemotherapy at what would be a normal dose for most individuals, severe vomiting, diarrhea, mouth sores, and other potentially life-threatening side effects such as myelosuppression can result. Therefore, screening for DPD status can identify patients who may suffer from these side effects, and alternative treatments can be instigated. Similarly, patients can be tested for activity of the UGT1A1 enzyme before treatment with irinotecan to minimize side effects (see Chapters 5 and 11). It is anticipated that many more pharmacogenomic markers of both efficacy and toxicity will be discovered in the future, and their use in clinical practice is likely to become widespread. This is discussed in more detail in Chapter 11.
Introduction to the disorders of purine and pyrimidine metabolism
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop
Dihydropyrimidine dehydrogenase is involved in the catabolism of 5 fluorouracil, and so patients receiving cancer chemotherapy are at risk for severe toxicity. We recommend screening for uracil-thyminuria in candidates for chemotherapy. A list of pyrimidine and other medications that might interfere with pyrimidine degradation is shown in Table 64.1.
Role of Genetic Variability in Breast Cancer Treatment Outcomes
Published in Brian Leyland-Jones, Pharmacogenetics of Breast Cancer, 2020
Kandace L. Amend, Ji-Yeob Choi, Christine B. Ambrosone
Because 5FU has a relatively narrow therapeutic index, toxicity increases as the dose is increased, and more than 80% of administered 5FU is catabolized by DPD (1). Patients with complete or partial deficiency of DPD often experience severe or even life-threatening toxicity after the administration of 5FU (60). At least 11 of 33 mutations identified in the dihydropyrimidine dehydrogenase (DPYD) gene have been detected in patients suffering from severe 5FU-associated toxicity (61–63).
DPYD and TYMS polymorphisms as predictors of 5 fluorouracil toxicity in colorectal cancer patients
Published in Journal of Chemotherapy, 2023
Yassine Khalij, Imtinen Belaid, Sana Chouchane, Dorra Amor, Asma Omezzine, Nabila Ben rejeb, Slim ben Ahmed, Ali Bouslama
Dihydropyrimidine dehydrogenase (DPD) deficiency is a significant determinant of severe 5-FU-associated toxicity [3]. DPD is the initial and rate-limiting enzyme in the degradation of 5-FU. Because DPD catabolizes more than 80% of the administered 5-FU, patients with a partial or complete DPD deficiency have a strongly reduced capacity to degrade 5-FU and, therefore, an increased likelihood of suffering from severe and sometimes fatal multi-organ toxicity [3, 4]. Many mutations and polymorphisms have been described in the gene (DPYD) encoding DPD, and ample evidence shows that carriers of the variant allele have an increased risk of developing toxicity [5, 6]. In principle, pharmacogenetics-guided dosing will enable the identification of patients at risk of developing severe toxicity before the start of fluoropyrimidine-based chemotherapy [7].
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.
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].