Cytidine deaminase residual activity in serum is a predictive marker of early severe toxicities in adults after gemcitabine-based chemotherapies

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Joseph CiccoliniCédric Mercier

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 di...Continue Reading

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