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(Tipifarnib, Zarnestraм) in Human Breast

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(Tipifarnib, Zarnestraм) in Human Breast ANTICANCER RESEARCH 25: 3215-3224 (2005) Biomarkers of Anticancer Activity of R115777 (Tipifarnib, Zarnestraì) in Human Breast Cancer Models In Vitro* ELZBIETA IZBICKA1, DAVID CAMPOS1, GILBERT CARRIZALES1 and AMITA PATNAIK2 1Cancer Therapy and Research Center, The Institute for Drug Development, 14960 Omicron Drive, San Antonio, TX, 78245; 2Cancer Therapy and Research Center, 7979 Wurzbach Drive, San Antonio, TX, 78229, U.S.A. Abstract. Background: Farnesyltransferase inhibitor R115777 Post-translational farnesylation of the Ras oncoprotein, (Tipifarnib, Zarnestraì) is active in breast cancer, but its efficacy catalyzed by farnesyltransferase (FTase), initiates in drug combinations has not been extensively investigated. translocation of Ras to the cell membrane and activation of Materials and Methods: The activity of R115777 and paclitaxel, the Ras signal transduction cascade. Substantial alone and in combination, was studied in the human breast experimental evidence has linked farnesylation of Ras with cancer cell lines, BT-474 (overexpressed HER2/neu) and MDA- a malignant phenotype. Farnesyltransferase inhibitors (FTIs) MB-231 (low HER2/neu), with cell viability and biomarkers for represent a novel class of anticancer drugs, that can inhibit farnesylation (HDJ-2, Rho B), tumor growth (Raf/MEK/ERK), malignant transformation with attenuated toxicity to normal survival (PI3K/Akt) and angiogenesis (VEGF, FGF-2, MMP-1, cells. The mechanism by which FTIs inhibit tumor growth is MMP-2, MMP-9) as the endpoints. Results: The drug more complex than originally thought. Although K-Ras can combination resulted in additive cytotoxicity. R115777 ± escape inhibition of processing by FTIs, tumors with paclitaxel inhibited HDJ-2 farnesylation, up-regulated RhoB, oncogenically mutated K-Ras proteins can still be inhibited transiently lowered (P)ERK/ERK and (P)Akt/Akt, reduced Raf- by FTI treatment. Furthermore, the Ras mutation status 1 and MEK, and inhibited secretion of VEGF and MMP-1. does not necessarily correlate with FTI sensitivity. Ras is Conclusion: The effect of R115777 on prenylation biomarkers is probably not the most important farnesylated protein whose consistent with its mechanism of action. The drug interfered with modification is inhibited as a result of FTI treatment. It is tumor growth, survival and angiogenesis pathways in breast likely that inhibition of the processing of other farnesylated cancer models with low or overexpressed HER2/neu receptor. proteins such as RhoB, a small GTPase, is responsible for The combination of R115777 with paclitaxel might offer clinical the apoptotic and antineoplastic responses of advantage over monotherapies. farnesyltransferase inhibitors (1). The effects of FTIs on the centromere-binding proteins CENP-E and CENP-F have been linked with cell cycle arrest, apoptosis and tumor regression in preclinical studies (2). Historically, FTIs have *Presented, in part, at the 36th Annual Meeting of the American been shown to suppress farnesylation of proteins DJ-1 and Society of Clinical Oncology, New Orleans, LA, May 2000; 11th DJ-2, homologs of the Escherichia coli heat shock protein Annual Meeting of NCI-AACR/EORTC, Amsterdam, Netherlands, DnaJ, which are ubiquitously expressed and post- November 2000; 92nd Annual Meeting of the American Association translationally modified by farnesylation. Human DJ-2 for Cancer Research, New Orleans, LA, March 2001; and at the AACR/NCI/EORTC International Conference on Molecular Targets (HDJ-2) has been used as one of surrogate biomarkers of and Cancer Therapeutics, Boston, MA, November 17-21, 2003. FTI activity in clinical trials (3). Downstream effectors of Ras, that bind Ras in a GTP- Abbreviations: DTT, dithiothreitol; PBMC, peripheral blood dependent manner through the effector domain loop, are mononuclear cells. likely to be affected by FTIs. They include the Raf family of proteins controlling apoptosis and cell cycle progression, Correspondence to: Elzbieta Izbicka, Cancer Therapy and Research protein kinases MEK and ERK involved in the control of Center, The Institute for Drug Development, 14960 Omicron Drive, San Antonio, TX, 78245, U.S.A. Tel: 210.677.3879, Fax: the transcription pathway, and others. Recently, the 210.677.0058, e-mail: [email protected] phosphoinositide 3-OH kinase/AKT2 pathway has been identified as a critical target for FTI-induced apoptosis. FTI Key Words: Farnesyltransferase inhibitor, R115777, Ras. inhibition of human tumor growth may be explained in 0250-7005/2005 $2.00+.40 3215 ANTICANCER RESEARCH 25: 3215-3224 (2005) Table I. Evaluation of cytotoxicity of R115777, R115776 and paclitaxel in human breast cancer cell lines in vitro. Agent BT-474 MDA-MB-231 R115777 5.4±0.2 ÌM 28.9±1.5 ÌM R115776 4.9±0.1 ÌM 23.9±0.5 ÌM Paclitaxel 2.7±0.2 nM 1.7±0.1 nM Figure 1. Structure of R115777. cancer cell lines, BT-474 (HER2/neu overexpression, relatively low EGFR, low levels of activated ras) (9, 10) and MDA-MB-231 (low level of HER2/neu, high EGFR expression, highly activated ras) (10-12), were used as model terms of induction of apoptosis through inhibition of PI systems. We examined the effects of R115777 alone and in 3-kinase/AKT2-mediated cell survival and adhesion pathway combination with paclitaxel on cell viability, prenylation of (4). FTIs have been shown to inhibit angiogenesis in vitro downstream targets, and select biomarkers for tumor growth, and in vivo. It has been proposed that the inhibition of survival and angiogenesis. The study demonstrated the ability oncogenic Ras by FTI can result in two events that alter of R115777 to interfere with tumor signaling pathways host-tumor interactions; up-regulation of Fas, rendering relevant for growth, survival and angiogenesis of cancer cells. tumors more sensitive to immune cytotoxic effector cells, The data suggest that R115777 in combination with paclitaxel and down-regulation of VEGF, which may inhibit tumor might offer an advantage over monotherapies in the angiogenesis (5). treatment of patients with HER2/neu-positive breast cancer. R115777 (Tipifarnib, Zarnestraì; Janssen Research Foundation, Titusville, NJ, USA), an orally bioavailable Materials and Methods quinolone analog of imidazole heterocyclics originally developed as antifungal agents (Figure 1), is a highly Cell culture. BT-474 and MDA-MB-231 human breast carcinoma specific nonpeptidomimetic competitive inhibitor of FTase cells (American Type Culture Collection, Rockville, MD, USA) (6). R115777 does not inhibit prenylation catalyzed by were maintained in a 1:1 mixture of DMEM: F12 (Mediatech Inc., geranylgeranyltransferase type I, which can alternatively Herndon, VA, USA), supplemented with 100 units/ml penicillin, prenylate K-Ras and RhoB. R115777 was shown to inhibit 100 Ìg/ml streptomycin, 2.5 Ìg/ml fungizone (Invitrogen Corp., the growth of a broad spectrum of human tumor models in Carlsbad, CA, USA) and 10% fetal bovine serum (Invitrogen vitro and in vivo, characterized by the wild-type or mutated Corp.) and incubated in a humidified incubator at 37ÆC in 5% CO2 /95% HEPA filtered air. Ras. The drug can be safely administered in clinical trials in patients with advanced solid malignancies and leukemia (7). Drug treatment. R115777, R115776 (Janssen Research Foundation, The most common toxicities include peripheral neuropathy, Titusville, NJ, USA) and paclitaxel (Sigma Chemical Co., St. Louis, fatigue and myelosuppression (8). In recent phase II clinical MO, USA) were prepared as stock solutions in dimethyl sulfoxide trials in patients with metastatic breast carcinoma, the drug (DMSO; Sigma Chemical Co.), diluted into media to the final showed reproducible single-agent activity, mainly in patients concentration of DMSO at 0.1%, and added once to the cells in with HER2-(c-erb-2, neu)-positive disease (7). The the exponential growth phase. HER2/neu receptor, overexpressed in 30% of human breast Growth inhibition assay. A MTS assay (13) was used to evaluate cancers, is associated with a poor prognosis for overall and drug growth inhibitory effects. Briefly, exponentially growing cells disease-free survival. in 100 mL of cell culture medium were plated on Day 0 in 96-well Since the best combinations incorporating trastuzumab microtiter plates at a density of 104 cells/well. On Day 1, the drugs (Herceptinì) yield response of 50%, it is rational to explore or the vehicle controls were added in triplicate to individual wells novel drug combinations as alternative therapeutic of the plates. The vehicle or the drugs at designated concentration approaches. The purpose of the present study was to examine were delivered in 100-ÌL aliquots of cell culture medium plus vehicle. The cells were incubated at 37ÆC and cultured for 72 h. a hypothesis that anticancer combination therapy with Then, 100 ÌL of medium was removed and the cells were incubated R115777 and paclitaxel will be more efficacious than single- with the addition of 20 ÌL MTS (1.9 mg/ml in PBS, pH 6.0), for drug therapy in patients with HER2/neu-expressing breast 1 h at 37ÆC. Absorbance was measured on a Tecan Plus microplate cancers. To mimic the clinical situation, two human breast reader at 490 nm. The IC50 values were determined by using the 3216 Izbicka et al: Biomarkers for Farnesyltransferase Inhibitor in Breast Cancer Prism GraphPad Software, Inc., San Diego, CA, USA. Drug ELISA. Cell culture media were collected at 24-h intervals during combinations were evaluated with cells plated as above in BT-474 4 days of drug treatment with the drugs added once at time=0. The and MDA-MB-231 with 10 nM and 5 nM paclitaxel, respectively. media was centrifuged to remove cellular debris and used for The corresponding concentrations of R115777 were 5 ÌM and 10 analysis of secreted proteins by ELISA using the following human- ÌM. Isoeffect plots were generated as described (14). The data are specific kits: MMP-2 (Amersham Biosciences), MMP-1, MMP-9, representative of at least three separate experiments. VEGF and basic FGF/FGF-2 (R&D Systems, Minneapolis, MN, USA), according to the suppliers’ instructions. All assays were Antibodies.
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