title: Bortezomib induces schedule-dependent modulation of gemcitabine pharmacokinetics and pharmacodynamics in non-small cell lung cancer and blood mononuclear cells.
abstract: 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.
authors.affiliation: Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Ceresa
authors.forename: Elisa
authors.initials: E
authors.lastname: Giovannetti
authors.forename: Jens
authors.initials: J
authors.lastname: Voortman
authors.forename: Adrie C
authors.initials: AC
authors.lastname: Laan
authors.forename: Richard
authors.initials: R
authors.lastname: Honeywell
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Giaccone
authors.forename: Godefridus J
authors.initials: GJ
authors.lastname: Peters
mesh_terms: D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D001897:Boronic Acids / Q000008:administration & dosage* / Q000633:toxicity; D000069286:Bortezomib; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D003842:Deoxycytidine Kinase / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D011719:Pyrazines / Q000008:administration & dosage* / Q000633:toxicity; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D011719:Pyrazines; D003841:Deoxycytidine; D000069286:Bortezomib; D003842:Deoxycytidine Kinase; D000093542:Gemcitabine