title: Toxic death case in a patient undergoing gemcitabine-based chemotherapy in relation with cytidine deaminase downregulation.
abstract: Gemcitabine is an antimetabolite drug used in the treatment of various solid tumours, including lung, pancreatic or gynaecological cancers. Innovative combinational strategies (e.g. gemcitabine+capecitabine or gemcitabine+oxaliplatin) make gemcitabine an extensively prescribed drug now. Gemcitabine is characterized by a narrow therapeutic index, and its liver elimination depends upon a key enzymatic step, driven by cytidine deaminase (CDA). CDA is prone to gene polymorphism, including the 208A>G mutation, which can result in marked enzymatic deficiency with subsequent impact on drug exposure levels and related toxicities. We have developed a simple and inexpensive method to determine phenotypically CDA status in cancer patients, as an attempt to detect those at risk upon gemcitabine intake. Conjointly to genotypic investigations, this method was used to phenotype, in a retrospective setting, a female patient displaying extremely severe, and eventually lethal, toxicities after administration of a standard gemcitabine/carboplatin protocol. Phenotypic investigation showed a marked CDA deficiency (-75%) in this patient when compared with a reference, nontoxic population. Genetic studies undertaken next to screen mutations, possibly at the origin of this deficiency, showed heterozygosity for the 79A>C single-point mutation, whereas surprisingly the canonical CDA 208A>G polymorphism was not found. Taken together, this case report demonstrates, for the first time, that CDA downregulation can lead to toxic-death in patients exposed to gemcitabine. Besides, we showed here that our cost-effective and simple phenotypic approach should enable, in the future, the detection of deficient patients at risk upon gemcitabine administration.
authors: EA3286, Pharmacokinetics Laboratory, Mediterranee University, Marseilles, France.
authors: Cédric
authors: C
authors: Mercier
authors: Caroline
authors: C
authors: Raynal
authors: Laetitia
authors: L
authors: Dahan
authors: Adrien
authors: A
authors: Ortiz
authors: Alexandre
authors: A
authors: Evrard
authors: Charlotte
authors: C
authors: Dupuis
authors: Aurore
authors: A
authors: Blesius
authors: Muriel
authors: M
authors: Duluc
authors: Fleur
authors: F
authors: Franceschini
authors: Sarah
authors: S
authors: Giacometti
authors: Sébastien
authors: S
authors: Salas
authors: Gérard
authors: G
authors: Milano
authors: Roger
authors: R
authors: Favre
authors: Jean-François
authors: JF
authors: Seitz
authors: Joseph
authors: J
authors: Ciccolini
mesh_terms: D000368:Aged; D003564:Cytidine Deaminase / Q000097:blood / Q000235:genetics*; D003841:Deoxycytidine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D015536:Down-Regulation / Q000187:drug effects*; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012016:Reference Values; D000093542:Gemcitabine
chemical_list: D003841:Deoxycytidine; D003564:Cytidine Deaminase; D000093542:Gemcitabine