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DPYD and Fluorouracil-Based Chemotherapy: Mini Review and Case Report

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DPYD and Fluorouracil-Based Chemotherapy: Mini Review and Case Report pharmaceutics Review DPYD and Fluorouracil-Based Chemotherapy: Mini Review and Case Report Theodore J. Wigle 1,2 , Elena V. Tsvetkova 3, Stephen A. Welch 3 and Richard B. Kim 1,2,* 1 Department of Physiology and Pharmacology, Schulich School of Medicine & Dentistry, Western University, London, ON N6A 3K7, Canada; [email protected] 2 Division of Clinical Pharmacology, Department of Medicine, Schulich School of Medicine & Dentistry, Western University, London, ON N6A 3K7, Canada 3 Division of Medical Oncology, Department of Oncology, Schulich School of Medicine & Dentistry, Western University, London, ON N6A 3K7, Canada; [email protected] (E.V.T.); [email protected] (S.A.W.) * Correspondence: [email protected]; Tel.: +519-685-8500 (ext. 33553); Fax: +519-663-3090 Received: 2 April 2019; Accepted: 23 April 2019; Published: 1 May 2019 Abstract: 5-Fluorouracil remains a foundational component of chemotherapy for solid tumour malignancies. While considered a generally safe and effective chemotherapeutic, 5-fluorouracil has demonstrated severe adverse event rates of up to 30%. Understanding the pharmacokinetics of 5-fluorouracil can improve the precision medicine approaches to this therapy. A single enzyme, dihydropyrimidine dehydrogenase (DPD), mediates 80% of 5-fluorouracil elimination, through hepatic metabolism. Importantly, it has been known for over 30-years that adverse events during 5-fluorouracil therapy are linked to high systemic exposure, and to those patients who exhibit DPD deficiency. To date, pre-treatment screening for DPD deficiency in patients with planned 5-fluorouracil-based therapy is not a standard of care. Here we provide a focused review of 5-fluorouracil metabolism, and the efforts to improve predictive dosing through screening for DPD deficiency. We also outline the history of key discoveries relating to DPD deficiency and include relevant information on the potential benefit of therapeutic drug monitoring of 5-fluorouracil. Finally, we present a brief case report that highlights a limitation of pharmacogenetics, where we carried out therapeutic drug monitoring of 5-fluorouracil in an orthotopic liver transplant recipient. This case supports the development of robust multimodality precision medicine services, capable of accommodating complex clinical dilemmas. Keywords: dihydropyrimidine dehydrogenase; DPYD; 5-fluorouracil; fluoropyrimidine; therapeutic drug monitoring; orthotopic liver transplant 1. Introduction to Fluoropyrimidines 5-fluorouracil (5-FU) has remained an important antineoplastic agent since the first description of the fluoropyrimidine class in 1957, and approval for testing in humans in 1962 [1,2]. Fluoropyrimidines, including 5-fluorouracil and its oral pre-prodrug capecitabine, serve as core components in the treatment of colorectal, pancreatic, gastric, breast, head and neck cancers [2–4]. However, the use of fluoropyrimidines carries an unfortunate risk of severe adverse events (AEs) of up to 30% [5,6]. Common AEs observed with fluoropyrimidine chemotherapies include non-bloody diarrhea, mucosal ulceration, immune suppression, and a painful skin condition known as hand-foot syndrome. Through optimizing the delivery methods, dosing schedules, and concomitant antineoplastic agents, a number of modern combination regimens with a fluoropyrimidine backbone have emerged including FOLFOX, FOLFIRINOX, CAPOX, and FLOT. Nevertheless, clinical trials using fluoropyrimidine-based chemotherapies continue to show severe AE rates up to 23% [7–10]. Accordingly, delineating the Pharmaceutics 2019, 11, 199; doi:10.3390/pharmaceutics11050199 www.mdpi.com/journal/pharmaceutics Pharmaceutics 2019, 11, x 2 of 17 Pharmaceutics 2019, 11, 199 2 of 17 using fluoropyrimidine-based chemotherapies continue to show severe AE rates up to 23% [7–10]. Accordingly, delineating the genetic and non-genetic determinants of fluoropyrimidine metabolism geneticand efficacy, and non-genetic is essential determinants to the ofimplementa fluoropyrimidinetion of metabolism precision and medicine efficacy, isapproaches essential to thefor implementationfluoropyrimidine-based of precision chemotherapy. medicine approaches for fluoropyrimidine-based chemotherapy. FluoropyrimidinesFluoropyrimidines are are an an antimetabolite antimetabolite class class of chemotherapeutic. of chemotherapeutic. As antimetabolites, As antimetabolites, they target they replicatingtarget replicating cells. Fluoropyrimidines cells. Fluoropyrimidines act primarily act through primarily conversion through of 5-FU conversion to fluoro-deoxyuridine of 5-FU to monophosphatefluoro-deoxyuridine (FdUMP). monophosphate FdUMP acts (FdUMP). as an irreversible FdUMP acts inhibitor as an ofirreversible the thymidylate inhibitor synthase of the enzymethymidylate this synthase is stabilized enzyme by this forming is stabilized a ternary by forming complex a ternary with complex the reduced with the folatereduced species folate methylene-tetrahydrofolate.species methylene-tetrahydrofolate. Thymidylate Thymidylate synthase synt playshase an importantplays an important role in regulating role in regulating the nucleotide the poolnucleotide by converting pool deoxyuridineby converting monophosphate deoxyuridine (dUMP) monophosphate to deoxythymidine (dUMP) monoposhpate to deoxythymidine (dTMP), providingmonoposhpate this pyrimidine (dTMP), buildingproviding block this for pyrimidine DNA synthesis. building When block thymidylate for DNA synthase synthesis. is inhibited, When thethymidylate buildup ofsynthase dUMP is nucleotides inhibited, the leads buildup to their of incorporationdUMP nucleotides into DNA, leads to which their overwhelmsincorporation DNA into repairDNA, mechanismswhich overwhelms and eventually DNA repair leads mechanisms to cell-death. and Thymidylate eventually leads synthase to cell-death. inhibition Thymidylate is the major canonicalsynthase inhibition mechanism is ofthe action major of fluoropyrimidines,canonical mechanis inm additionof action they of fluoropy can exertrimidines, antineoplastic in addition effects throughthey can at exert least antineoplastic two additional effects pathways. through First, at activeleast two fluoropyrimidine additional pathways. (FdUMP) First, can also active be incorrectlyfluoropyrimidine incorporated (FdUMP) into can DNA also in be place incorrectly of dTMP in leadingcorporated to both into singleDNA strandin place and of dTMP double leading strand breaks.to both Thesingle resultant strand and DNA double damage strand induces breaks. cell The cycle resultant arrest and DNA death. damage Second, induces 5-FU cell is converted cycle arrest to fluorouridineand death. Second, triphosphate 5-FU (FUTP)is converted and incorrectly to fluorouridine incorporated triphosphate in RNA. The(FUTP) combination and incorrectly of RNA damage,incorporated DNA in damage, RNA. The and combination inhibition of of cell RNA cycle damage, provide theDNA mechanistic damage, and basis inhibition for the antineoplastic of cell cycle eprovideffects of the fluoropyrimidines mechanistic basis (Figure for the1, for antineoplastic review see [ 11 effects]). The of antimetabolite fluoropyrimidines properties (Figure of 5-FU1, for support review thesee antineoplastic[11]). The antimetabolite effects, but a lackproperties of specificity of 5-FU underpins support thethe AEs antineoplastic seen with this effects, therapy. but The a lack classic of fluoropyrimidinespecificity underpins toxicities the AEs occur seen in rapidlywith this regenerating therapy. The tissues classic such fluoropyrimidine as the mucosal toxicities membranes, occur skin, in andrapidly bone regenerating marrow. Therefore, tissues such the as eff theective mucosal but nonspecific membranes, nature skin, ofand fluoropyrimidines bone marrow. Therefore, is the likely the culpriteffective for but numerous nonspecific AEs. nature Appropriately of fluoropyrimidines balancing the therapeuticis the likely benefit culprit vs. for toxicity numerous of this classAEs. ofAppropriately antineoplastic balancing drugs has the proved therapeutic to be benefit a major vs challenge, toxicity of requiring this class a of detailed antineoplastic understanding drugs has of theproved pharmacology. to be a major challenge, requiring a detailed understanding of the pharmacology. FigureFigure 1.1. A simplifiedsimplified metabolism of 5-fluorouracil5-fluorouracil (5-FU). ThymidylateThymidylate phosphorylasephosphorylase (TYMP) generatesgenerates fluorouridinefluorouridine (FUDR), (FUDR), which which is converted is conv toerted Fluoro-deoxyuridine to Fluoro-deoxyuridine monophosphate monophosphate (FdUMP) by(FdUMP) thymidylate by thymidylate kinase (TYMK). kinase FdUMP (TYMK). inhibits FdUMP thymidylate inhibits thymidylate synthase (TYMS) synthase causing (TYMS) an imbalance causing an of deoxyuridineimbalance of deoxyuridine monophosphate monophosphate (dUMP) and deoxythymidine (dUMP) and deoxythymidine monophosphate monophosphate (dTMP). Incorporation (dTMP). ofIncorporation dUMP into of DNA dUMP causes into damage DNA causes and leads damage to cell and death. leads 5-FUto cell is death. converted 5-FUto is fluorouridineconverted to monophosphatefluorouridine monophosphate (FUMP) by uridine (FUMP) monophosphate by uridine monophosphate synthetase (UMPS) synthetase with further (UMPS) phosphorylation with further byphosphorylation uridine kinase by (UK). uridine Incorporation kinase (UK). of Incorporat fluorinatedion nucleotides of fluorinated (FUTP nucleo or FdUMP)tides (FUTP into or both FdUMP) RNA andinto DNAboth respectivelyRNA
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