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Gene polymorphisms, pharmacokinetics, and hematological toxicity in advanced non-small-cell lung cancer patients receiving cisplatin/gemcitabine

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Abstract

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/m2 i.v. followed by cisplatin 75 mg/m2. 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.

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Acknowledgments

M. Joerger is supported by a fellowship grant funded by the European Society of Medical Oncology, by a Novartis-UICC Translational Cancer Research Fellowship funded by Novartis AG, and by a research grant from the Swiss National Science Foundation (PBBSB-102331).

Conflict of interest

None of the authors has any former or present conflict of interest related to this study.

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Authors and Affiliations

  1. Department of Pharmacy and Pharmacology, Slotervaart Hospital/The Netherlands Cancer Institute, Amsterdam, The Netherlands

    M. Joerger, R. S. Jansen, L. D. Vainchtein, H. Rosing, A. D. R. Huitema & J. H. Beijnen

  2. Department of Clinical Pharmacology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands

    M. Joerger, J. H. Beijnen & J. H. M. Schellens

  3. Department of Oncology and Hematology, Cantonal Hospital, Rorschacherstrasse 95, 9007, St.Gallen, Switzerland

    M. Joerger

  4. Department of Thoracic Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

    J. A. Burgers & P. Baas

  5. Department of Molecular Biology, Slotervaart Hospital/The Netherlands Cancer Institute, Amsterdam, The Netherlands

    V. D. Doodeman & P. H. M. Smits

  6. Division of Biomedical Analysis, Department of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands

    J. H. Beijnen & J. H. M. Schellens

  7. Department of Drug Toxicology, Utrecht University, Utrecht, The Netherlands

    J. H. M. Schellens

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  1. M. Joerger
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  2. J. A. Burgers
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  3. P. Baas
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  4. V. D. Doodeman
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  5. P. H. M. Smits
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  6. R. S. Jansen
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  7. L. D. Vainchtein
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  8. H. Rosing
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  9. A. D. R. Huitema
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  10. J. H. Beijnen
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  11. J. H. M. Schellens
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Correspondence to M. Joerger.

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Joerger, M., Burgers, J.A., Baas, P. et al. Gene polymorphisms, pharmacokinetics, and hematological toxicity in advanced non-small-cell lung cancer patients receiving cisplatin/gemcitabine. Cancer Chemother Pharmacol 69, 25–33 (2012). https://doi.org/10.1007/s00280-011-1670-4

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  • DOI: https://doi.org/10.1007/s00280-011-1670-4

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