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BMC Cancer

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Open Access 01-12-2004 | Research article

Microarray analysis reveals genetic pathways modulated by tipifarnib in acute myeloid leukemia

Authors: Mitch Raponi, Robert T Belly, Judith E Karp, Jeffrey E Lancet, David Atkins, Yixin Wang

Published in: BMC Cancer | Issue 1/2004

Abstract

Background

Farnesyl protein transferase inhibitors (FTIs) were originally developed to inhibit oncogenic ras, however it is now clear that there are several other potential targets for this drug class. The FTI tipifarnib (ZARNESTRA™, R115777) has recently demonstrated clinical responses in adults with refractory and relapsed acute leukemias. This study was conducted to identify genetic markers and pathways that are regulated by tipifarnib in acute myeloid leukemia (AML).

Methods

Tipifarnib-mediated gene expression changes in 3 AML cell lines and bone marrow samples from two patients with AML were analyzed on a cDNA microarray containing approximately 7000 human genes. Pathways associated with these expression changes were identified using the Ingenuity Pathway Analysis tool.

Results

The expression analysis identified a common set of genes that were regulated by tipifarnib in three leukemic cell lines and in leukemic blast cells isolated from two patients who had been treated with tipifarnib. Association of modulated genes with biological functional groups identified several pathways affected by tipifarnib including cell signaling, cytoskeletal organization, immunity, and apoptosis. Gene expression changes were verified in a subset of genes using real time RT-PCR. Additionally, regulation of apoptotic genes was found to correlate with increased Annexin V staining in the THP-1 cell line but not in the HL-60 cell line.

Conclusions

The genetic networks derived from these studies illuminate some of the biological pathways affected by FTI treatment while providing a proof of principle for identifying candidate genes that might be used as surrogate biomarkers of drug activity.

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The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2407/4/56/prepub

Title: Microarray analysis reveals genetic pathways modulated by tipifarnib in acute myeloid leukemia
Authors: Mitch Raponi
Robert T Belly
Judith E Karp
Jeffrey E Lancet
David Atkins
Yixin Wang
Publication date: 01-12-2004
Publisher: BioMed Central
Published in: BMC Cancer / Issue 1/2004
Electronic ISSN: 1471-2407
DOI: https://doi.org/10.1186/1471-2407-4-56

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