Enhancement of the therapeutic efficacy of taxol by the mitogen-activated protein kinase kinase inhibitor CI-1040 in nude mice bearing human heterotransplants

Hayley M. McDaid, Lluis Lopez-Barcons, Aaron Grossman, Marie Lia, Steven Keller, Roman Perez-Soler, Susan Band Horwitz

Research output: Contribution to journalArticle

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Abstract

Taxol may contribute to intrinsic chemoresistance by activating the mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) cytoprotective pathway in human cancer cell lines and tumors. We have previously shown additivity between Taxol and the MEK inhibitor, U0126 in human cancer cell lines. Here, the combination of Taxol with an orally bioavailable MEK inhibitor, CI-1040, was evaluated in human lung tumors heterotransplanted into nude mice. Unlike xenograft models that are derived from cells with multiple genetic alterations due to prolonged passage, heterotransplanted tumor models are more clinically relevant. Combined treatment with both drugs resulted in inhibition of tumor growth in all models and tumor regressions in three of four models tested, supporting our previous observation that Taxol's efficacy is potentiated by MEK inhibition. Concurrent administration was superior to intermittent dosing. Pharmacodynamic assessments of tumors indicated that suppression of MEK was associated with induction of S473 phosphorylated Akt and reduced proliferation in the combination groups relative to single agents, in addition to suppression of fibroblast growth factor-mediated angiogenesis and reduced expression of vascular endothelial growth factor. These findings are significant and indicate that this combination may have broad therapeutic applications in a diverse range of lung tumors with different intrinsic chemosensitivities.

Original languageEnglish (US)
Pages (from-to)2854-2860
Number of pages7
JournalCancer Research
Volume65
Issue number7
DOIs
StatePublished - Apr 1 2005

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Mitogen-Activated Protein Kinase Kinases
Paclitaxel
Heterografts
Nude Mice
Neoplasms
Therapeutics
Lung
Fibroblast Growth Factors
2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide
Extracellular Signal-Regulated MAP Kinases
Tumor Cell Line
Vascular Endothelial Growth Factor A
Cell Line
Growth
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Enhancement of the therapeutic efficacy of taxol by the mitogen-activated protein kinase kinase inhibitor CI-1040 in nude mice bearing human heterotransplants. / McDaid, Hayley M.; Lopez-Barcons, Lluis; Grossman, Aaron; Lia, Marie; Keller, Steven; Perez-Soler, Roman; Band Horwitz, Susan.

In: Cancer Research, Vol. 65, No. 7, 01.04.2005, p. 2854-2860.

Research output: Contribution to journalArticle

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