Comparison of potential markers of farnesyltransferase inhibition

Alex Adjei, Jenny N. Davis, Charles Erlichman, Phyllis A. Svingen, Scott H Kaufmann

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Abstract

Farnesyltransferase inhibitors (FTIs) were developed to target abnormal signaling pathways that are commonly activated in neoplastic cells. Five FTIs have recently undergone Phase I testing; and two are currently in Phase II clinical trials. As part of the development of these agents, there has been interest in determining their cellular effects in the clinical setting. Several approaches have been proposed, including measurement of FT enzymatic activity, evaluation of the processing of FT polypeptide substrates, and assessment of the accumulation of p21(waf1). In the present study, a number of these assays have been compared in four cultured human neoplastic cell lines of different histology (A549, HCT116, BxPC-3, and MCF-7) after treatment with the nonpeptidomimetic FTI SCH66336 and the peptidomimetic inhibitor FTI-277. Immunoblotting studies failed to demonstrate a mobility shift in ras proteins or increased accumulation of p21(waf1) after treatment with these agents. In contrast, drug-induced increases in the slower migrating, unprocessed species of the chaperone protein HDJ-2 and the intranuclear intermediate filament protein lamin A were detected in all four cell lines after treatment with either agent. Unprocessed forms of both polypeptides accumulated in noncycling as well as cycling cells. The precursor peptide that is present in prelamin A but absent from mature lamin A could be readily detected by immunohistochemistry in noncycling cells with a peptide-specific antiserum. Our results indicate that unprocessed HDJ-2 and prelamin A should be suitable markers of FT inhibition in clinical samples.

Original languageEnglish (US)
Pages (from-to)2318-2325
Number of pages8
JournalClinical Cancer Research
Volume6
Issue number6
StatePublished - Jun 2000

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ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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