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Impact of imatinib on the pharmacokinetics and in vivo efficacy of etoposide and/or ifosfamide

BACKGROUND: Using a human small cell lung cancer (SCLC) xenografted in nude mice, we have previously reported enhanced tumor growth inhibition following chemotherapy in combination with imatinib (STI571). We therefore investigated the in vivo impact of imatinib on the pharmacokinetics and efficacy o...

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Autores principales: Rezaï, Keyvan, Lokiec, François, Grandjean, Isabelle, Weill, Sophie, de Cremoux, Patricia, Bordier, Vincent, Ekue, Richard, Garcia, Mickael, Poupon, Marie-France, Decaudin, Didier
Formato: Texto
Lenguaje:English
Publicado: BioMed Central 2007
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2180168/
https://www.ncbi.nlm.nih.gov/pubmed/17963518
http://dx.doi.org/10.1186/1471-2210-7-13
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author Rezaï, Keyvan
Lokiec, François
Grandjean, Isabelle
Weill, Sophie
de Cremoux, Patricia
Bordier, Vincent
Ekue, Richard
Garcia, Mickael
Poupon, Marie-France
Decaudin, Didier
author_facet Rezaï, Keyvan
Lokiec, François
Grandjean, Isabelle
Weill, Sophie
de Cremoux, Patricia
Bordier, Vincent
Ekue, Richard
Garcia, Mickael
Poupon, Marie-France
Decaudin, Didier
author_sort Rezaï, Keyvan
collection PubMed
description BACKGROUND: Using a human small cell lung cancer (SCLC) xenografted in nude mice, we have previously reported enhanced tumor growth inhibition following chemotherapy in combination with imatinib (STI571). We therefore investigated the in vivo impact of imatinib on the pharmacokinetics and efficacy of chemotherapy. METHODS: Two different human tumors were used: SCLC6 small cell lung cancer xenografted in nude mice, and LY-3 EBV-associated human B-cell lymphoma xenografted in SCID mice. Plasma, urine, and fecal concentrations of etoposide (VP16) were determined by a validated high performance liquid chromatography method. Plasma concentrations of ifosfamidewere determined by a validated gas chromatography assay with nitrogen-phosphorus detection. RESULTS: Slight tumor growth inhibition was induced by imatinib administered alone in one in vivo EBV-associated B-cell lymphomatous xenograft. In contrast, an increase of the chemotherapy-induced antitumor effect was observed in the lymphoma model but not in a small cell lung cancer model when mice bearing human xenografted tumors were treated concomitantly by imatinib and chemotherapy. This antitumor effect was not influenced by concomitant administration of fluconazole. The AUC0-3 h (Area Under the concentration-time Curve) of etoposide was increased when mice were treated with etoposide + imatinib due to decreased fecal excretion. In contrast, imatinib did not appear to influence the urinary excretion of etoposide, and concomitant administration of the CYP3A4 inhibitor, fluconazole, with imatinib did not modify the pharmacokinetics of etoposide plus imatinib alone. CONCLUSION: Altogether, these results therefore justify further prospective phase I and II clinical trials with combinations of etoposide-based chemotherapy and imatinib in patients with certain cancers, such as malignant lymphoma, with careful toxicologic monitoring.
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spelling pubmed-21801682008-01-09 Impact of imatinib on the pharmacokinetics and in vivo efficacy of etoposide and/or ifosfamide Rezaï, Keyvan Lokiec, François Grandjean, Isabelle Weill, Sophie de Cremoux, Patricia Bordier, Vincent Ekue, Richard Garcia, Mickael Poupon, Marie-France Decaudin, Didier BMC Pharmacol Research Article BACKGROUND: Using a human small cell lung cancer (SCLC) xenografted in nude mice, we have previously reported enhanced tumor growth inhibition following chemotherapy in combination with imatinib (STI571). We therefore investigated the in vivo impact of imatinib on the pharmacokinetics and efficacy of chemotherapy. METHODS: Two different human tumors were used: SCLC6 small cell lung cancer xenografted in nude mice, and LY-3 EBV-associated human B-cell lymphoma xenografted in SCID mice. Plasma, urine, and fecal concentrations of etoposide (VP16) were determined by a validated high performance liquid chromatography method. Plasma concentrations of ifosfamidewere determined by a validated gas chromatography assay with nitrogen-phosphorus detection. RESULTS: Slight tumor growth inhibition was induced by imatinib administered alone in one in vivo EBV-associated B-cell lymphomatous xenograft. In contrast, an increase of the chemotherapy-induced antitumor effect was observed in the lymphoma model but not in a small cell lung cancer model when mice bearing human xenografted tumors were treated concomitantly by imatinib and chemotherapy. This antitumor effect was not influenced by concomitant administration of fluconazole. The AUC0-3 h (Area Under the concentration-time Curve) of etoposide was increased when mice were treated with etoposide + imatinib due to decreased fecal excretion. In contrast, imatinib did not appear to influence the urinary excretion of etoposide, and concomitant administration of the CYP3A4 inhibitor, fluconazole, with imatinib did not modify the pharmacokinetics of etoposide plus imatinib alone. CONCLUSION: Altogether, these results therefore justify further prospective phase I and II clinical trials with combinations of etoposide-based chemotherapy and imatinib in patients with certain cancers, such as malignant lymphoma, with careful toxicologic monitoring. BioMed Central 2007-10-27 /pmc/articles/PMC2180168/ /pubmed/17963518 http://dx.doi.org/10.1186/1471-2210-7-13 Text en Copyright © 2007 Rezaï et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( (http://creativecommons.org/licenses/by/2.0) ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Rezaï, Keyvan
Lokiec, François
Grandjean, Isabelle
Weill, Sophie
de Cremoux, Patricia
Bordier, Vincent
Ekue, Richard
Garcia, Mickael
Poupon, Marie-France
Decaudin, Didier
Impact of imatinib on the pharmacokinetics and in vivo efficacy of etoposide and/or ifosfamide
title Impact of imatinib on the pharmacokinetics and in vivo efficacy of etoposide and/or ifosfamide
title_full Impact of imatinib on the pharmacokinetics and in vivo efficacy of etoposide and/or ifosfamide
title_fullStr Impact of imatinib on the pharmacokinetics and in vivo efficacy of etoposide and/or ifosfamide
title_full_unstemmed Impact of imatinib on the pharmacokinetics and in vivo efficacy of etoposide and/or ifosfamide
title_short Impact of imatinib on the pharmacokinetics and in vivo efficacy of etoposide and/or ifosfamide
title_sort impact of imatinib on the pharmacokinetics and in vivo efficacy of etoposide and/or ifosfamide
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2180168/
https://www.ncbi.nlm.nih.gov/pubmed/17963518
http://dx.doi.org/10.1186/1471-2210-7-13
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