Bortezomib induces schedule-dependent modulation of gemcitabine pharmacokinetics and pharmacodynamics in non-small cell lung cancer and blood mononuclear cells.
Mol Cancer Ther
; 8(5): 1026-36, 2009 May.
Article
em En
| MEDLINE
| ID: mdl-19383850
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 â 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 â gemcitabine/cisplatin schedule appeared a safe and active combination for the treatment of advanced NSCLC and the bortezomib â 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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Pirazinas
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Ácidos Borônicos
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Leucócitos Mononucleares
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Carcinoma Pulmonar de Células não Pequenas
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Desoxicitidina
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Neoplasias Pulmonares
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Antineoplásicos
Limite:
Humans
Idioma:
En
Revista:
Mol Cancer Ther
Ano de publicação:
2009
Tipo de documento:
Article