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Antimetabolites
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
5-Fluorouracil (5-FU) (Figure 3.11), a fluoropyrimidine approved in 1962, is administered by intravenous injection or infusion, or by intra-arterial infusion, for the treatment of some solid tumors, including gastrointestinal tract and breast cancers, and in combination with folinic acid for advanced colorectal cancer. Oral administration has been tried but found to be unpredictable. It is also used topically for the treatment of superficial malignant and premalignant skin lesions, where a 5% cream (i.e., EfudexTM) is highly effective.
Lipid Nanocarriers for Oligonucleotide Delivery to the Brain
Published in Carla Vitorino, Andreia Jorge, Alberto Pais, Nanoparticles for Brain Drug Delivery, 2021
Andreia F. Jorge, Santiago Grijalvo, Alberto Pais, Ramón Eritja
The antitumoural action of the decamer FdU10 composed by 10 monomers of 5-fluoro-2/-deoxyuridine monophosphate (FdU) has been demonstrated in in vivo preclinical models of acute myeloid leukaemia [93], acute lymphocytic leukaemia [94], prostate cancer [95] and GBM [96]. Once internalised, the metabolites of the polymeric fluoropyrimidine drug bind covalently to the nucleotide-binding site of thymidylate synthase (TS), inhibiting in this way the synthesis of deoxythymidine monophosphate (dTMP) and, consequently, triggering an apoptosis mechanism called ‘thymineless cell death’ [97]. FdU10 has displayed minimal penetrance of the BBB, but through intracerebral administration, it has been demonstrated to be safe and efficient in reducing tumour progression [96]. Histological analyses revealed almost complete suppression of tumours in a GBM mouse orthotopic xenograft model. Of note, recently DNA nanoassemblies were designed to hide in scaffold polymeric fluoropyrimidine strands, representing a promising approach for cancer therapy [98, 99].
Mid Common Bile Duct Cholangiocarcinoma Involving the Portal Vein and Right Branch of the Hepatic Artery
Published in Savio George Barreto, Shailesh V. Shrikhande, Dilemmas in Abdominal Surgery, 2020
Charles W. Kimbrough, Timothy M. Pawlik
Even after margin-negative resection, cholangiocarcinoma is associated with high rates of locoregional and distant recurrence and adjuvant therapy should be considered. The National Comprehensive Cancer Network (NCCN) guidelines recommend adjuvant therapy for patients with gross residual disease (R2), microscopically positive margins (R1), or lymph node metastasis. Common regimens include fluoropyrimidine or gemcitabine-based chemotherapy, either alone or with fluoropyrimidine-based chemoradiation. Following results from the BILCAP-2 trial (NCT00363584), many patients now receive adjuvant capecitabine. While observation or adjuvant therapy are options for patients with node-negative disease and microscopically negative margins, patients should generally be referred to medical oncology for discussion of additional treatment.
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].
Incidence and risk markers of 5-fluorouracil and capecitabine cardiotoxicity in patients with colorectal cancer
Published in Acta Oncologica, 2020
Anne Dyhl-Polk, Merete Vaage-Nilsen, Morten Schou, Kirsten Kjeldgaard Vistisen, Cecilia Margareta Lund, Thomas Kümler, Jon Michael Appel, Dorte Lisbet Nielsen
Overall, the patterns and incidences of cardiac events in this study agree with findings in previous studies [12], although some studies have reported higher incidences of cardiac arrhythmias [21,30,31]. The observed incidence of sudden death or cardiac arrest in 1 per 250 treated patients is high but in line with previous studies. The cause of sudden death was unclear in most patients because autopsy was only available in one case. Hence, we might have overestimated the incidence of sudden death caused by 5-FU and capecitabine, since some of the patients could have died from a pulmonary embolus or other complications. However, the continuous reporting of a temporal association between fluoropyrimidine treatment and sudden death or cardiac arrest suggests a causal relation between the treatment and serious adverse outcomes. Furthermore, in three patients that were successfully resuscitated, no other reasons for cardiac arrest were identified and coronary angiography revealed no stenosis.
Pharmacotherapeutic considerations for elderly patients with colorectal cancer
Published in Expert Opinion on Pharmacotherapy, 2019
5-FU reports exclusively in the elderly are available in several evaluations, and infusional 5-FU is considered beneficial and generally well tolerated in the elderly [41,70,71]. We feel 5-FU is a safe option for most elderly patients with some considerations, as those with a significant cardiovascular history should have a cardiology clearance prior to therapy. Patients identified as frail should receive a dose reduction upfront, frequent AE monitoring, and consideration dihydropyrimidine dehydrogenase deficiency testing to avoid extreme toxicity. Capecitabine in the elderly shows similar efficacy with more dose-dependent AEs (diarrhea; hand-foot syndrome) particularly in those oldest in age and unfit [41,70]. We consider the same cautions with 5-FU for capecitabine elderly use but additionally recommend avoidance in patients on warfarin or who have poor renal function. These patients should be given 5-FU when a fluoropyrimidine is needed. Patients with complex medication lists (≥8–10 medications) or any cognitive decline that limit adherence should avoid capecitabine use given that an intravenous alternative exists and would eliminate these concerns.