title: Cytidine deaminase residual activity in serum is a predictive marker of early severe toxicities in adults after gemcitabine-based chemotherapies.
abstract: PURPOSE Anticipating toxicities with gemcitabine is an ongoing story, and deregulation in cytidine deaminase (CDA) could be associated with increased risk of developing early severe toxicities on drug exposure. PATIENTS AND METHODS A simple test to evaluate CDA phenotypic status was first validated in an animal model investigating relationships between CDA activity and gemcitabine-related toxicities. Next, relevance of this test as a marker for toxicities was retrospectively tested in a first subset of 64 adult patients treated with gemcitabine alone, then it was tested in a larger group of 130 patients who received gemcitabine either alone or combined with other drugs and in 20 children. Additionally, search for the 435 T>C, 208 G>A and 79 A>C mutations on the CDA gene was performed. Results In mice, CDA deficiency impacted on gemcitabine pharmacokinetics and had subsequent lethal toxicities. In human, 12% of adult patients experienced early severe toxicities after gemcitabine administration. A significant difference in CDA activities was observed between patients with and without toxicities (1.2 +/- 0.8 U/mg v 4 +/- 2.6 U/mg; P < .01). Conversely, no genotype-to-phenotype relationships were found. Of note, the patients who displayed particularly reduced CDA activity all experienced strong toxicities. Gemcitabine was well tolerated in children, and no CDA deficiency was evidenced. CONCLUSION Our data suggest that CDA functional testing could be a simple and easy marker to discriminate adult patients at risk of developing severe toxicities with gemcitabine. Particularly, this study demonstrates that CDA deficiency, found in 7% of adult patients, is associated with a maximum risk of developing early severe toxicities with gemcitabine.
authors.affiliation: Md, Medical Oncology Unit, La Timone University Hospital, 205 Rue St Pierre, 13385, Marseille, cedex 05, France.
authors.forename: Joseph
authors.initials: J
authors.lastname: Ciccolini
authors.forename: Laetitia
authors.initials: L
authors.lastname: Dahan
authors.forename: Nicolas
authors.initials: N
authors.lastname: André
authors.forename: Alexandre
authors.initials: A
authors.lastname: Evrard
authors.forename: Muriel
authors.initials: M
authors.lastname: Duluc
authors.forename: Aurore
authors.initials: A
authors.lastname: Blesius
authors.forename: Chenguang
authors.initials: C
authors.lastname: Yang
authors.forename: Sarah
authors.initials: S
authors.lastname: Giacometti
authors.forename: Caroline
authors.initials: C
authors.lastname: Brunet
authors.forename: Caroline
authors.initials: C
authors.lastname: Raynal
authors.forename: Adrien
authors.initials: A
authors.lastname: Ortiz
authors.forename: Nicolas
authors.initials: N
authors.lastname: Frances
authors.forename: Athanassios
authors.initials: A
authors.lastname: Iliadis
authors.forename: Florence
authors.initials: F
authors.lastname: Duffaud
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Seitz
authors.forename: Cédric
authors.initials: C
authors.lastname: Mercier
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects*; D015415:Biomarkers; D002648:Child; D002675:Child, Preschool; D003564:Cytidine Deaminase / Q000097:blood*; D003841:Deoxycytidine / Q000009:adverse effects / Q000031:analogs & derivatives*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D015415:Biomarkers; D003841:Deoxycytidine; D003564:Cytidine Deaminase; D000093542:Gemcitabine