Bortezomib induces schedule-dependent modulation of gemcitabine pharmacokinetics and pharmacodynamics in non-small cell lung cancer and blood mononuclear cells
| Autor: | Elisa Giovannetti, Cecilia Ceresa, Richard J. Honeywell, Jens Voortman, Godefridus J. Peters, Giuseppe Giaccone, A.C. Laan |
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| Přispěvatelé: | Medical oncology laboratory, Medical oncology, Internal medicine, CCA - Innovative therapy, Ceresa, C, Giovannetti, E, Voortman, J, Laan, A, Honeywell, R, Giaccone, G, Peters, G |
| Rok vydání: | 2009 |
| Předmět: |
Cancer Research
Lung Neoplasms Antineoplastic Agents Pharmacology Deoxycytidine Bortezomib chemistry.chemical_compound Pharmacokinetics BIO/16 - ANATOMIA UMANA immune system diseases hemic and lymphatic diseases Carcinoma Non-Small-Cell Lung Cell Line Tumor Antineoplastic Combined Chemotherapy Protocols Deoxycytidine Kinase medicine Humans Drug Interactions Lung cancer neoplasms Cisplatin Dose-Response Relationship Drug Chemistry Deoxycytidine kinase medicine.disease Boronic Acids Gemcitabine Gene Expression Regulation Neoplastic Oncology Pharmacodynamics Pyrazines Leukocytes Mononuclear bortezomib gemcitabine non small cell lung cancer medicine.drug |
| Zdroj: | Molecular Cancer Therapeutics, 8(5), 1026-1036. American Association for Cancer Research Inc. Ceresa, C, Giovannetti, E, Voortman, J, Laan, A, Honeywell, R J, Giaccone, G & Peters, G J 2009, ' Bortezomib induces schedule-dependent modulation of gemcitabine pharmacokinetics and pharmacodynamics in non-small cell lung cancer and blood mononuclear cells ', Molecular Cancer Therapeutics, vol. 8, no. 5, pp. 1026-1036 . https://doi.org/10.1158/1535-7163.MCT-08-0700 |
| ISSN: | 1538-8514 1535-7163 |
| DOI: | 10.1158/1535-7163.MCT-08-0700 |
| Popis: | Bortezomib combination with gemcitabine/cisplatin in patients with advanced tumors, predominantly non-small cell lung cancer (NSCLC), showed an unexpected transient drop in the deoxycytidine plasma levels, a marker for gemcitabine activity. This study investigates the pharmacokinetic/pharmacodynamic effect of bortezomib on gemcitabine in NSCLC and peripheral blood mononuclear cells (PBMC). Gemcitabine metabolites, including difluoro-dCTP (dFdCTP), were studied in PBMCs from bortezomib/gemcitabine/cisplatin-treated patients and from volunteers and NSCLC cells (H460 and SW1573) exposed to 4 h simultaneous or sequential treatments of gemcitabine (50 μmol/L, 4 h) and bortezomib (100 nmol/L, 2 h). Gemcitabine total phosphate levels measured by liquid chromatography-tandem mass spectrometry in PBMCs from bortezomib/gemcitabine/cisplatin-treated patients were strongly reduced after 90 min (−82.2%) up to 4 h post-gemcitabine infusion compared with gemcitabine/cisplatin-treated patients. Accordingly, bortezomib/gemcitabine combinations reduced dFdCTP in PBMCs treated ex vivo. Surprisingly, differential effects were observed in NSCLC cells. dFdCTP decreased after 4 h following gemcitabine removal in H460 but continued to increase for 24 h in SW1573. However, dFdCTP significantly increased (2-fold) in both cell lines in the bortezomib→gemcitabine exposure, coinciding with a major reduction in cell growth compared with single drugs, and the highest increase of deoxycytidine kinase expression, possibly mediated via E2F-1. Bortezomib affects differently gemcitabine pharmacokinetics/pharmacodynamics in PBMCs and NSCLC cells, suggesting that PBMCs are not adequate to evaluate the anticancer activity of bortezomib/gemcitabine combinations. The bortezomib→gemcitabine/cisplatin schedule appeared a safe and active combination for the treatment of advanced NSCLC and the bortezomib→gemcitabine was the most cytotoxic combination in NSCLC cells. The increase of deoxycytidine kinase and dFdCTP might contribute to this synergistic interaction and supports its further clinical investigation. [Mol Cancer Ther 2009;8(5):1026–36] |
| Databáze: | OpenAIRE |
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