5-FU-induced neurotoxicity in cancer patients with profound DPD deficiency syndrome: a report of two cases

Cordier, Pierre-Yves; Nau, André; Ciccolini, Joseph; Oliver, Manuela; Mercier, Cédric; Lacarelle, Bruno; Peytel, E.

doi:10.1007/s00280-011-1666-0

Cited by 39 publications

(32 citation statements)

References 13 publications

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“…TPP deficiency can indirectly result in reduced GABA levels and decrease the seizure threshold [78,79]. Furthermore, 5-FU neurotoxicity is associated with dihydropyrimidine dehydrogenase (DPD) deficiency [80]. Fujiwaki et al [81] found that DPD gene expression in epithelial ovarian cancers was significantly lower than that of healthy ovaries.…”

Section: Pathogenesismentioning

confidence: 98%

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Epilepsy in women with gynecologic malignancies

Yang

Wang

2014

Expert Review of Neurotherapeutics

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Women with gynecologic malignancies are a population with various risk factors for epilepsy. Gynecologic malignancies can substantially affect daily life, even if the tumor is well controlled. Gynecologic malignancies may cause brain metastasis, paraneoplastic neurological disorders, or leptomeningeal carcinomatosis, which potentially directly cause seizures and epilepsy. Moreover, metabolic disorders, central nervous system infections, cerebrovascular complications, and chemotherapeutic drugs can indirectly induce ictus. Radiotherapy of brain metastases can also lead to seizure and epilepsy. Understanding these pathogenic mechanisms may provide novel viewpoints or methods for diagnosis, prevention and treatment of epilepsy associated with gynecologic malignancies. In this article, we extensively review the related literature regarding potential aetiologies, their mechanisms, clinical features, diagnosis and treatment.

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Section: Pathogenesismentioning

confidence: 98%

“…DPD is an enzyme involved in the initial step in the catabolism of 5-FU. DPD deficiency results in lower clearance and toxic accumulation of 5-FU, which may cause neurotoxic symptoms including seizures to increase [80].…”

Section: Pathogenesismentioning

confidence: 99%

Epilepsy in women with gynecologic malignancies

Yang

Wang

2014

Expert Review of Neurotherapeutics

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“…The natural history of early‐onset severe toxicity from 5‐FU and capecitabine is well documented . Patients with an exaggerated sensitivity to 5‐FU or capecitabine may quickly develop severe, life‐threatening toxicities during or after administration, which can manifest as severe forms of common toxicities such as mucositis and cytopenias but can also include central neurotoxicity and acute cardiomyopathy.…”

Section: Introductionmentioning

confidence: 99%

Emergency use of uridine triacetate for the prevention and treatment of life‐threatening 5‐fluorouracil and capecitabine toxicity

Wee

Saif

El‐Rayes

et al. 2016

Cancer

101

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BACKGROUNDIncreased susceptibility to 5‐fluorouracil (5‐FU)/capecitabine can lead to rapidly occurring toxicity caused by impaired clearance, dihydropyrimidine dehydrogenase deficiency, and other genetic variations in the enzymes that metabolize 5‐FU. Life‐threatening 5‐FU overdoses occur because of infusion pump errors, dosage miscalculations, and accidental or suicidal ingestion of capecitabine. Uridine triacetate (Vistogard) was approved in 2015 for adult and pediatric patients who exhibit early‐onset severe or life‐threatening 5‐FU/capecitabine toxicities or present with an overdose. Uridine triacetate delivers high concentrations of uridine, which competes with toxic 5‐FU metabolites.METHODSIn 2 open‐label clinical studies, patients who presented with a 5‐FU/capecitabine overdose or an early onset of severe toxicities were treated. Patients received uridine triacetate as soon as possible (most within the first 96 hours after 5‐FU/capecitabine). Outcomes included survival, resumption of chemotherapy, and safety. Their survival was compared with the survival of a historical cohort of overdose patients who received only supportive care.RESULTSA total of 137 of 142 overdose patients (96%) treated with uridine triacetate survived and had a rapid reversal of severe acute cardiotoxicity and neurotoxicity; in addition, mucositis and leukopenia were prevented, or the patients recovered from them. In the historical cohort, 21 of 25 patients (84%) died. Among the 141 uridine triacetate–treated overdose patients with a diagnosis of cancer (the noncancer patients included 6 intentional or accidental pediatric overdoses), 53 resumed chemotherapy in < 30 days (median time after 5‐FU, 19.6 days), and this indicated a rapid recovery from toxicity. Adverse reactions in patients receiving uridine triacetate included vomiting (8.1%), nausea (4.6%), and diarrhea (3.5%).CONCLUSIONSIn these studies, uridine triacetate was a safe and effective lifesaving antidote for capecitabine and 5‐FU overexposure, and it facilitated the rapid resumption of chemotherapy. Cancer 2017;123:345–356. © 2016 American Cancer Society.

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“…In particular, they inhibit enzymes involved in the synthesis of nucleic acids 5 and nucleotides, 6 signal DNA damage upon their incorporation, 7 obstruct DNA repair, 8 and trigger apoptosis by directly affecting mitochondria. 9 Problematically, the most active clinically approved antimetabolite drugs elicit deadly side effects 10,11 as they also affect rapidly proliferating normal human cells, lymphocytes, 12 and sometimes even non-dividing cells, such as neurons, 13 which substantially narrows their therapeutic windows. Additionally, their efficiency is limited to a relatively short list of malignancies that are predominantly hematological, 14 although gemcitabine 15 has proven to be effective against several solid tumors.…”

Section: Introductionmentioning

confidence: 99%

Base-modified thymidines capable of terminating DNA synthesis are novel bioactive compounds with activity in cancer cells

Borland

AbdulSalam

Solivio

et al. 2015

Bioorganic & Medicinal Chemistry

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Current FDA-approved chemotherapeutic antimetabolites elicit severe side effects that warrant their improvement; therefore, we designed compounds with mechanisms of action focusing on inhibiting DNA replication rather than targeting multiple pathways. We previously discovered that 5-(α-substituted-2-nitrobenzyloxy)methyluridine-5′-triphosphates were exquisite DNA synthesis terminators; therefore, we synthesized a library of 35 thymidine analogs and evaluated their activity using an MTT cell viability assay of MCF7 breast cancer cells chosen for their vulnerability to these nucleoside derivatives. Compound 3a, having an α-tert-butyl-2-nitro-4-(phenyl)alkynylbenzyloxy group, showed an IC50 of 9 ± 1 μM. The compound is more selective for cancer cells than for fibroblast cells compared with 5-fluorouracil. Treatment of MCF7 cells with 3a elicits the DNA damage response as indicated by phosphorylation of γ-H2A. A primer extension assay of the 5′-triphosphate of 3a revealed that 3aTP is more likely to inhibit DNA polymerase than to lead to termination events upon incorporation into the DNA replication fork.

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5-FU-induced neurotoxicity in cancer patients with profound DPD deficiency syndrome: a report of two cases

Cited by 39 publications

References 13 publications

Epilepsy in women with gynecologic malignancies

Epilepsy in women with gynecologic malignancies

Emergency use of uridine triacetate for the prevention and treatment of life‐threatening 5‐fluorouracil and capecitabine toxicity

Base-modified thymidines capable of terminating DNA synthesis are novel bioactive compounds with activity in cancer cells

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