BACKGROUND: This study quantified the impact of drug pathway-associated genetic variants on the pharmacokinetics (PK) of gemcitabine and cisplatin in patients with advanced non-small-cell lung cancer (NSCLC). METHODS: Thirty-seven patients with advanced NSCLC were sampled for plasma concentrations of gemcitabine, difluoro-deoxy uridine (dFdU), intracellular gemcitabine triphosphates (dFdCTP), and unbound platinum concentrations after gemcitabine 1,250 mg/m(2) i.v. followed by cisplatin 75 mg/m(2). We analyzed 13 germline single nucleotide polymorphisms and one deletion-glutathione S-transferase (GST) M1-within six drug pathway-associated genes (GSTM1, GSTP1, cytidine deaminase (CDA), solute carrier (SLC) 28A1, SLC28A2, and deoxycytidine kinase). PK models were fitted to the data using nonlinear mixed-effects modeling, and genetic data were tested on drug PK and hematological toxicity. RESULTS: Patients carrying the nonsynonymous CDA SNP 79A >C (CDA*2) had a 21% lower gemcitabine clearance as compared to wild-type patients (outcomes and complications.0.0009), but the risk for chemotherapy-associated neutropenia (61% vs. 32%, P = 0.07) and severe neutropenia (17% vs. 5%, P = 0.26) was not significantly higher. Other gene polymorphisms were not associated with drug PK parameters or hematological toxicity. The known functional mutant variant CDA*3 was not found in any of the patients. CONCLUSIONS: Although the mutant CDA*2 allele results in an increased exposure to gemcitabine in Caucasian patients, this study gives no definite conclusion on the clinical relevance of this finding. Further studies should look into the relationship between CDA genotypes, plasmatic CDA activity, and clinical outcome in patients receiving gemcitabine-based chemotherapy.
BACKGROUND: This study quantified the impact of drug pathway-associated genetic variants on the pharmacokinetics (PK) of gemcitabine and cisplatin in patients with advanced non-small-cell lung cancer (NSCLC). METHODS: Thirty-seven patients with advanced NSCLC were sampled for plasma concentrations of gemcitabine, difluoro-deoxy uridine (dFdU), intracellular gemcitabine triphosphates (dFdCTP), and unbound platinum concentrations after gemcitabine 1,250 mg/m(2) i.v. followed by cisplatin 75 mg/m(2). We analyzed 13 germline single nucleotide polymorphisms and one deletion-glutathione S-transferase (GST) M1-within six drug pathway-associated genes (GSTM1, GSTP1, cytidine deaminase (CDA), solute carrier (SLC) 28A1, SLC28A2, and deoxycytidine kinase). PK models were fitted to the data using nonlinear mixed-effects modeling, and genetic data were tested on drug PK and hematological toxicity. RESULTS:Patients carrying the nonsynonymous CDA SNP 79A >C (CDA*2) had a 21% lower gemcitabine clearance as compared to wild-type patients (outcomes and complications.0.0009), but the risk for chemotherapy-associated neutropenia (61% vs. 32%, P = 0.07) and severe neutropenia (17% vs. 5%, P = 0.26) was not significantly higher. Other gene polymorphisms were not associated with drug PK parameters or hematological toxicity. The known functional mutant variant CDA*3 was not found in any of the patients. CONCLUSIONS: Although the mutant CDA*2 allele results in an increased exposure to gemcitabine in Caucasian patients, this study gives no definite conclusion on the clinical relevance of this finding. Further studies should look into the relationship between CDA genotypes, plasmatic CDA activity, and clinical outcome in patients receiving gemcitabine-based chemotherapy.
Authors: Federico Innocenti; Chen Jiang; Alexander B Sibley; Stefanie Denning; Amy S Etheridge; Dorothy Watson; Donna Niedzwiecki; Ace J Hatch; Herbert I Hurwitz; Andrew B Nixon; Yoichi Furukawa; Michiaki Kubo; Daniel J Crona; Hedy L Kindler; Howard L McLeod; Mark J Ratain; Kouros Owzar Journal: Pharmacogenet Genomics Date: 2019-08 Impact factor: 2.089
Authors: René J Boosman; Marie-Rose B S Crombag; Nielka P van Erp; Jos H Beijnen; Neeltje Steeghs; Alwin D R Huitema Journal: Cancer Chemother Pharmacol Date: 2022-04-15 Impact factor: 3.288
Authors: Marie-Rose B S Crombag; Aurelia H M de Vries Schultink; Jan H M Schellens; Jos H Beijnen; Alwin D R Huitema Journal: Drugs Aging Date: 2014-10 Impact factor: 3.923
Authors: A Khatri; B W Williams; J Fisher; R C Brundage; V J Gurvich; L G Lis; K M Skubitz; A Z Dudek; E W Greeno; R A Kratzke; J K Lamba; M N Kirstein Journal: Br J Cancer Date: 2013-12-03 Impact factor: 7.640