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Jos H. Beijnen - One of the best experts on this subject based on the ideXlab platform.
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phase i study of Lonafarnib sch66336 in combination with trastuzumab plus paclitaxel in her2 neu overexpressing breast cancer eortc study 16023
Cancer Chemotherapy and Pharmacology, 2013Co-Authors: Bojana Milojkovic Kerklaan, Anne-sophie Govaerts, Sandrine Marreaud, Hilde Rosing, Veronique Dieras, Christophe Le Tourneau, Alwin D. R. Huitema, Jos H. Beijnen, Marja Merguiroelvink, Martine PiccartgebhartAbstract:Purpose This phase I study was performed to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), safety profile, recommended dose for phase II studies, the pharmacokinetics, and antitumor activity of the combination of Lonafarnib (farnesyl transferase inhibitor), trastuzumab, and paclitaxel in Her2-positive advanced breast cancer.
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Phase I study of Lonafarnib (SCH66336) in combination with trastuzumab plus paclitaxel in Her2/neu overexpressing breast cancer: EORTC study 16023
Cancer Chemotherapy and Pharmacology, 2013Co-Authors: Bojana Milojkovic Kerklaan, Marja Mergui-roelvink, Anne-sophie Govaerts, Sandrine Marreaud, Hilde Rosing, Veronique Dieras, Christophe Le Tourneau, Alwin D. R. Huitema, Jos H. Beijnen, Martine J. Piccart-gebhartAbstract:PurposeThis phase I study was performed to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), safety profile, recommended dose for phase II studies, the pharmacokinetics, and antitumor activity of the combination of Lonafarnib (farnesyl transferase inhibitor), trastuzumab, and paclitaxel in Her2-positive advanced breast cancer.MethodsTwenty-three patients with Her2-overexpressing breast cancer received in the first cycle paclitaxel and trastuzumab and from cycle 2 onwards Lonafarnib which was added to the combination. Dose-limiting toxicity (DLT) was determined during the second cycle.ResultsThe MTD and the recommended dose for phase II trials are Lonafarnib: 250 mg/day [125 mg/bi-daily (BID)] continuously, paclitaxel: 175 mg/m² 3-h infusion every 3 weeks, and trastuzumab: 4 mg/kg loading dose and 2 mg/kg/week thereafter. The most frequently observed adverse events starting from cycle 1 onwards were alopecia, myalgia, sensory neuropathy, fatigue, arthralgia, leukocytopenia, and neutropenia. From cycle 2 onwards, additional adverse events appeared, such as diarrhea, nausea, dyspepsia, vomiting, and allergy. The mean systemic exposures of both Lonafarnib and paclitaxel through all dose levels were higher in the regimen with all three study medications but with no statistically significant difference. Preliminary antitumor activity (CR + PR) was observed in 58 % of all patients.ConclusionLonafarnib can be safely combined and tolerated with full doses of paclitaxel and trastuzumab in Her2-positive advanced breast cancer patients. Promising preliminary antitumor activity warrants further evaluation of Lonafarnib in combination with paclitaxel and trastuzumab in Her2-positive breast cancer.
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Phase i study of Lonafarnib (SCH66336) in combination with trastuzumab plus paclitaxel in Her2/neu overexpressing breast cancer: EORTC study 16023
Cancer chemotherapy and pharmacology, 2012Co-Authors: Bojana Milojkovic Kerklaan, Marja Mergui-roelvink, Anne-sophie Govaerts, Sandrine Marreaud, Hilde Rosing, Veronique Dieras, Christophe Le Tourneau, Alwin D. R. Huitema, Jos H. Beijnen, Martine J. Piccart-gebhartAbstract:Purpose This phase I study was performed to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), safety profile, recommended dose for phase II studies, the pharmacokinetics, and antitumor activity of the combination of Lonafarnib (farnesyl transferase inhibitor), trastuzumab, and paclitaxel in Her2-positive advanced breast cancer.
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Quantitative analysis of the farnesyl transferase inhibitor Lonafarnib (Sarasar™, SCH66336) in human plasma using high‐performance liquid chromatography coupled with tandem mass spectrometry
Rapid communications in mass spectrometry : RCM, 2005Co-Authors: Natalie M. G. M. Appels, Hilde Rosing, Maria J. Van Maanen, Jan H.m. Schellens, Jos H. BeijnenAbstract:Lonafarnib is a novel anticancer drug that inhibits farnesyl transferase. To assess its pharmacokinetic properties, we developed a sensitive and quantitative assay using liquid chromatography coupled with tandem mass spectrometry for the determination of Lonafarnib levels in human plasma. Sample pretreatment consisted of the addition of an isotopically labeled internal standard and protein precipitation with acetonitrile using 100 µL plasma. Chromatographic separation was performed on an Inertsil ODS-3 analytical column (50 × 2.1 mm i.d., particle size 5 µm) with acetonitrile/water/formic acid (50:50:0.05, v/v/v) as the mobile phase, at a flow rate of 0.2 mL/min. The analytical run time was 8 min. An API365 triple quadrupole mass spectrometer was used for specific and sensitive detection. It was operated in the positive ion mode and multiple reaction monitoring was used for drug quantification. The method was validated using a concentration range of 2.5 to 2500 ng/mL Lonafarnib. Validation of the assay was performed according to the most recent FDA guidelines for bioanalytical method validation and all results were within the requirements. The described method was successfully applied to support a clinical phase I trial with Lonafarnib. Copyright © 2005 John Wiley & Sons, Ltd.
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quantitative analysis of the farnesyl transferase inhibitor Lonafarnib sarasar sch66336 in human plasma using high performance liquid chromatography coupled with tandem mass spectrometry
Rapid Communications in Mass Spectrometry, 2005Co-Authors: Natalie M. G. M. Appels, Hilde Rosing, Jos H. Beijnen, Maria J. Van Maanen, Jan H.m. SchellensAbstract:Lonafarnib is a novel anticancer drug that inhibits farnesyl transferase. To assess its pharmacokinetic properties, we developed a sensitive and quantitative assay using liquid chromatography coupled with tandem mass spectrometry for the determination of Lonafarnib levels in human plasma. Sample pretreatment consisted of the addition of an isotopically labeled internal standard and protein precipitation with acetonitrile using 100 µL plasma. Chromatographic separation was performed on an Inertsil ODS-3 analytical column (50 × 2.1 mm i.d., particle size 5 µm) with acetonitrile/water/formic acid (50:50:0.05, v/v/v) as the mobile phase, at a flow rate of 0.2 mL/min. The analytical run time was 8 min. An API365 triple quadrupole mass spectrometer was used for specific and sensitive detection. It was operated in the positive ion mode and multiple reaction monitoring was used for drug quantification. The method was validated using a concentration range of 2.5 to 2500 ng/mL Lonafarnib. Validation of the assay was performed according to the most recent FDA guidelines for bioanalytical method validation and all results were within the requirements. The described method was successfully applied to support a clinical phase I trial with Lonafarnib. Copyright © 2005 John Wiley & Sons, Ltd.
Fadlo R Khuri - One of the best experts on this subject based on the ideXlab platform.
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a phase ii study of Lonafarnib sch66336 in patients with chemorefractory advanced squamous cell carcinoma of the head and neck
American Journal of Clinical Oncology, 2009Co-Authors: Emer O Hanrahan, Fadlo R Khuri, Bonnie S Glisson, Merrill S. Kies, Lawrence E. Ginsberg, Mylene T. Truong, W. K. Hong, Lei Feng, Hai T Tran, Edward S KimAbstract:Objective: Treatment options for recurrent squamous cell carcinoma of the head and neck (SCCHN) following platinum-based therapy are limited. Lonafarnib is a potent, specific inhibitor of farnesyl transferase that demonstrated marked antitumor activity as monotherapy in treatment-naive SCCHN in a phase Ib study. A phase II study of Lonafarnib was conducted to determine its efficacy and safety in patients with recurrent, platinum-refractory SCCHN. Methods: This was an open-label, phase II, single-center study in patients with recurrent SCCHN after platinum-based therapy. A Simon 2-stage design was used, with a plan to close the study to further accrual if <2 of the first 15 patients had objective responses. Patients were treated with lonafamib 200 mg twice daily (b.i.d.) by mouth continuously in 4-week cycles. Results: Fifteen patients with baseline Eastern Cooperative Oncology Group PS 0―1 and median age 57 years were enrolled. Twelve patients had received at least 2 previous chemotherapy regimens. Median duration of treatment with Lonafarnib was 61 days. No objective response was observed. Seven (47%) patients maintained stable disease through ≥3 cycles of therapy. Median time to progression and survival time were 2.04 and 9.17 months, respectively. Most treatment-related toxicities were grade 1―2, and there were no treatment-related deaths. Conclusions: Lonafarnib at a dose of 200 mg b.i.d. was well-tolerated. However, there were no objective responses observed in the first 15 patients enrolled in this study, and the study was closed to further accrual, as per predefined criteria. Further evaluation of Lonafarnib in platinum-refractory SCCHN is not planned.
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A phase II study of Lonafarnib (SCH66336) in patients with chemorefractory, advanced squamous cell carcinoma of the head and neck.
American journal of clinical oncology, 2009Co-Authors: Emer O Hanrahan, Fadlo R Khuri, Bonnie S Glisson, Merrill S. Kies, Lawrence E. Ginsberg, Mylene T. Truong, W. K. Hong, Lei Feng, Hai T Tran, Edward S KimAbstract:Objective: Treatment options for recurrent squamous cell carcinoma of the head and neck (SCCHN) following platinum-based therapy are limited. Lonafarnib is a potent, specific inhibitor of farnesyl transferase that demonstrated marked antitumor activity as monotherapy in treatment-naive SCCHN in a phase Ib study. A phase II study of Lonafarnib was conducted to determine its efficacy and safety in patients with recurrent, platinum-refractory SCCHN. Methods: This was an open-label, phase II, single-center study in patients with recurrent SCCHN after platinum-based therapy. A Simon 2-stage design was used, with a plan to close the study to further accrual if
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the farnesyltransferase inhibitor Lonafarnib induces ccaat enhancer binding protein homologous protein dependent expression of death receptor 5 leading to induction of apoptosis in human cancer cells
Journal of Biological Chemistry, 2007Co-Authors: Shiyong Sun, Xiangguo Liu, Wei Zou, Ping Yue, Adam I Marcus, Fadlo R KhuriAbstract:Pre-clinical studies have demonstrated that farnesyltransferase inhibitors (FTIs) induce growth arrest or apoptosis in various human cancer cells independently of Ras mutations. However, the underlying mechanism remains unknown. Death receptor 5 (DR5) is a pro-apoptotic protein involved in mediating the extrinsic apoptotic pathway. Its role in FTI-induced apoptosis has not been reported. In this study, we investigated the modulation of DR5 by the FTI Lonafarnib and the involvement of DR5 up-regulation in FTI-induced apoptosis. Lonafarnib activated caspase-8 and its downstream caspases, whereas the caspase-8-specific inhibitor benzyloxycarbonyl-Ile-Glu(methoxy)-Thr-Asp(methoxy)-fluoromethyl ketone or small interfering RNA abrogated Lonafarnib-induced apoptosis, indicating that Lonafarnib induces caspase-8-dependent apoptosis. Lonafarnib up-regulated DR5 expression, increased cell-surface DR5 distribution, and enhanced tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis. Overexpression of a dominant-negative Fas-associated death domain mutant or silencing of DR5 expression using small interfering RNA attenuated Lonafarnib-induced apoptosis. These results indicate a critical role of the DR5-mediated extrinsic apoptotic pathway in Lonafarnib-induced apoptosis. By analyzing the DR5 promoter, we found that Lonafarnib induced a CCAAT/enhancer-binding protein homologous protein (CHOP)-dependent transactivation of the DR5 promoter. Lonafarnib increased CHOP expression, whereas silencing of CHOP expression abrogated Lonafarnib-induced DR5 expression. These results thus indicate that Lonafarnib induces CHOP-dependent DR5 up-regulation. We conclude that CHOP-dependent DR5 up-regulation contributes to Lonafarnib-induced apoptosis.
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The Farnesyltransferase Inhibitor Lonafarnib Induces CCAAT/Enhancer-binding Protein Homologous Protein-dependent Expression of Death Receptor 5, Leading to Induction of Apoptosis in Human Cancer Cells
The Journal of biological chemistry, 2007Co-Authors: Shiyong Sun, Xiangguo Liu, Wei Zou, Ping Yue, Adam I Marcus, Fadlo R KhuriAbstract:Pre-clinical studies have demonstrated that farnesyltransferase inhibitors (FTIs) induce growth arrest or apoptosis in various human cancer cells independently of Ras mutations. However, the underlying mechanism remains unknown. Death receptor 5 (DR5) is a pro-apoptotic protein involved in mediating the extrinsic apoptotic pathway. Its role in FTI-induced apoptosis has not been reported. In this study, we investigated the modulation of DR5 by the FTI Lonafarnib and the involvement of DR5 up-regulation in FTI-induced apoptosis. Lonafarnib activated caspase-8 and its downstream caspases, whereas the caspase-8-specific inhibitor benzyloxycarbonyl-Ile-Glu(methoxy)-Thr-Asp(methoxy)-fluoromethyl ketone or small interfering RNA abrogated Lonafarnib-induced apoptosis, indicating that Lonafarnib induces caspase-8-dependent apoptosis. Lonafarnib up-regulated DR5 expression, increased cell-surface DR5 distribution, and enhanced tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis. Overexpression of a dominant-negative Fas-associated death domain mutant or silencing of DR5 expression using small interfering RNA attenuated Lonafarnib-induced apoptosis. These results indicate a critical role of the DR5-mediated extrinsic apoptotic pathway in Lonafarnib-induced apoptosis. By analyzing the DR5 promoter, we found that Lonafarnib induced a CCAAT/enhancer-binding protein homologous protein (CHOP)-dependent transactivation of the DR5 promoter. Lonafarnib increased CHOP expression, whereas silencing of CHOP expression abrogated Lonafarnib-induced DR5 expression. These results thus indicate that Lonafarnib induces CHOP-dependent DR5 up-regulation. We conclude that CHOP-dependent DR5 up-regulation contributes to Lonafarnib-induced apoptosis.
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Farnesyl transferase inhibitors impair chromosomal maintenance in cell lines and human tumors by compromising CENP-E and CENP-F function.
Molecular cancer therapeutics, 2007Co-Authors: Katherine Schafer-hales, Fadlo R Khuri, Adel K. El-naggar, Paraskevi Giannakakou, Jonathan Iaconelli, James P. Snyder, Andrew Prussia, James H. Nettles, Adam I MarcusAbstract:Farnesyl transferase inhibitors (FTI) exhibit anticancer activity as a single agent in preclinical studies and show promise in combination with other therapeutics in clinical trials. Previous studies show that FTIs arrest cancer cells in mitosis; however, the mechanism by which this occurs is unclear. Here, we observed that treatment of various cancer cell lines with the FTI Lonafarnib caused mitotic chromosomal alignment defects, leaving cells in a pseudometaphase state, whereby both aligned chromosomes and chromosomes juxtaposed to the spindle poles (termed ‘‘lagging chromosomes’’) were observed in the same cell. To determine how this occurs, we investigated the functionality of two farnesylated mitotic proteins, CENPE and CENP-F, which mediate chromosomal capture and alignment. The data show that Lonafarnib in proliferating cancer cells depletes CENP-E and CENP-F from metaphase but not prometaphase kinetochores. Loss of CENP-E and CENP-F metaphase localization triggered aberrant chromosomal maintenance, causing aligned chromosomes to be prematurely released from the spindle equator and become lagging chromosomes, resulting in a mitotic delay. Furthermore, Lonafarnib treatment reduces sister kinetochore tension and activates the BubR1 spindle checkpoint, suggesting that farnesylation of CENP-E and CENP-F is critical for their functionality in maintaining kinetochoremicrotubule interactions. Importantly, apparently similar chromosomal alignment defects were observed in head and neck tumors samples from a phase I trial with Lonafarnib, providing support that Lonafarnib disrupts chromosomal maintenance in human cancers. Lastly, to examine how farnesylation could regulate CENP-E in mediating kinetochore-microtubule attachments, we examined possible docking motifs of a farnesyl group on the outer surface of the microtubule. This analysis revealed three hydrophobic patches on the tubulin dimer for insertion of a farnesyl group, alluding to the possibility of an association between a farnesyl group and the microtubule. [Mol Cancer Ther 2007;6(4):1317 – 28]
Adam I Marcus - One of the best experts on this subject based on the ideXlab platform.
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the farnesyltransferase inhibitor Lonafarnib induces ccaat enhancer binding protein homologous protein dependent expression of death receptor 5 leading to induction of apoptosis in human cancer cells
Journal of Biological Chemistry, 2007Co-Authors: Shiyong Sun, Xiangguo Liu, Wei Zou, Ping Yue, Adam I Marcus, Fadlo R KhuriAbstract:Pre-clinical studies have demonstrated that farnesyltransferase inhibitors (FTIs) induce growth arrest or apoptosis in various human cancer cells independently of Ras mutations. However, the underlying mechanism remains unknown. Death receptor 5 (DR5) is a pro-apoptotic protein involved in mediating the extrinsic apoptotic pathway. Its role in FTI-induced apoptosis has not been reported. In this study, we investigated the modulation of DR5 by the FTI Lonafarnib and the involvement of DR5 up-regulation in FTI-induced apoptosis. Lonafarnib activated caspase-8 and its downstream caspases, whereas the caspase-8-specific inhibitor benzyloxycarbonyl-Ile-Glu(methoxy)-Thr-Asp(methoxy)-fluoromethyl ketone or small interfering RNA abrogated Lonafarnib-induced apoptosis, indicating that Lonafarnib induces caspase-8-dependent apoptosis. Lonafarnib up-regulated DR5 expression, increased cell-surface DR5 distribution, and enhanced tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis. Overexpression of a dominant-negative Fas-associated death domain mutant or silencing of DR5 expression using small interfering RNA attenuated Lonafarnib-induced apoptosis. These results indicate a critical role of the DR5-mediated extrinsic apoptotic pathway in Lonafarnib-induced apoptosis. By analyzing the DR5 promoter, we found that Lonafarnib induced a CCAAT/enhancer-binding protein homologous protein (CHOP)-dependent transactivation of the DR5 promoter. Lonafarnib increased CHOP expression, whereas silencing of CHOP expression abrogated Lonafarnib-induced DR5 expression. These results thus indicate that Lonafarnib induces CHOP-dependent DR5 up-regulation. We conclude that CHOP-dependent DR5 up-regulation contributes to Lonafarnib-induced apoptosis.
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The Farnesyltransferase Inhibitor Lonafarnib Induces CCAAT/Enhancer-binding Protein Homologous Protein-dependent Expression of Death Receptor 5, Leading to Induction of Apoptosis in Human Cancer Cells
The Journal of biological chemistry, 2007Co-Authors: Shiyong Sun, Xiangguo Liu, Wei Zou, Ping Yue, Adam I Marcus, Fadlo R KhuriAbstract:Pre-clinical studies have demonstrated that farnesyltransferase inhibitors (FTIs) induce growth arrest or apoptosis in various human cancer cells independently of Ras mutations. However, the underlying mechanism remains unknown. Death receptor 5 (DR5) is a pro-apoptotic protein involved in mediating the extrinsic apoptotic pathway. Its role in FTI-induced apoptosis has not been reported. In this study, we investigated the modulation of DR5 by the FTI Lonafarnib and the involvement of DR5 up-regulation in FTI-induced apoptosis. Lonafarnib activated caspase-8 and its downstream caspases, whereas the caspase-8-specific inhibitor benzyloxycarbonyl-Ile-Glu(methoxy)-Thr-Asp(methoxy)-fluoromethyl ketone or small interfering RNA abrogated Lonafarnib-induced apoptosis, indicating that Lonafarnib induces caspase-8-dependent apoptosis. Lonafarnib up-regulated DR5 expression, increased cell-surface DR5 distribution, and enhanced tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis. Overexpression of a dominant-negative Fas-associated death domain mutant or silencing of DR5 expression using small interfering RNA attenuated Lonafarnib-induced apoptosis. These results indicate a critical role of the DR5-mediated extrinsic apoptotic pathway in Lonafarnib-induced apoptosis. By analyzing the DR5 promoter, we found that Lonafarnib induced a CCAAT/enhancer-binding protein homologous protein (CHOP)-dependent transactivation of the DR5 promoter. Lonafarnib increased CHOP expression, whereas silencing of CHOP expression abrogated Lonafarnib-induced DR5 expression. These results thus indicate that Lonafarnib induces CHOP-dependent DR5 up-regulation. We conclude that CHOP-dependent DR5 up-regulation contributes to Lonafarnib-induced apoptosis.
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Farnesyl transferase inhibitors impair chromosomal maintenance in cell lines and human tumors by compromising CENP-E and CENP-F function.
Molecular cancer therapeutics, 2007Co-Authors: Katherine Schafer-hales, Fadlo R Khuri, Adel K. El-naggar, Paraskevi Giannakakou, Jonathan Iaconelli, James P. Snyder, Andrew Prussia, James H. Nettles, Adam I MarcusAbstract:Farnesyl transferase inhibitors (FTI) exhibit anticancer activity as a single agent in preclinical studies and show promise in combination with other therapeutics in clinical trials. Previous studies show that FTIs arrest cancer cells in mitosis; however, the mechanism by which this occurs is unclear. Here, we observed that treatment of various cancer cell lines with the FTI Lonafarnib caused mitotic chromosomal alignment defects, leaving cells in a pseudometaphase state, whereby both aligned chromosomes and chromosomes juxtaposed to the spindle poles (termed ‘‘lagging chromosomes’’) were observed in the same cell. To determine how this occurs, we investigated the functionality of two farnesylated mitotic proteins, CENPE and CENP-F, which mediate chromosomal capture and alignment. The data show that Lonafarnib in proliferating cancer cells depletes CENP-E and CENP-F from metaphase but not prometaphase kinetochores. Loss of CENP-E and CENP-F metaphase localization triggered aberrant chromosomal maintenance, causing aligned chromosomes to be prematurely released from the spindle equator and become lagging chromosomes, resulting in a mitotic delay. Furthermore, Lonafarnib treatment reduces sister kinetochore tension and activates the BubR1 spindle checkpoint, suggesting that farnesylation of CENP-E and CENP-F is critical for their functionality in maintaining kinetochoremicrotubule interactions. Importantly, apparently similar chromosomal alignment defects were observed in head and neck tumors samples from a phase I trial with Lonafarnib, providing support that Lonafarnib disrupts chromosomal maintenance in human cancers. Lastly, to examine how farnesylation could regulate CENP-E in mediating kinetochore-microtubule attachments, we examined possible docking motifs of a farnesyl group on the outer surface of the microtubule. This analysis revealed three hydrophobic patches on the tubulin dimer for insertion of a farnesyl group, alluding to the possibility of an association between a farnesyl group and the microtubule. [Mol Cancer Ther 2007;6(4):1317 – 28]
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The Synergistic Combination of the Farnesyl Transferase Inhibitor Lonafarnib and Paclitaxel Enhances Tubulin Acetylation and Requires a Functional Tubulin Deacetylase
Cancer research, 2005Co-Authors: Adam I Marcus, Fadlo R Khuri, Jun Zhou, Aurora O'brate, Ernest Hamel, Jason Y.y. Wong, Michael C. Nivens, Adel K. El-naggar, Tso-pang Yao, Paraskevi GiannakakouAbstract:Farnesyl transferase (FT) inhibitors (FTI) are anticancer agents developed to target oncogenic Ras proteins by inhibiting Ras farnesylation. FTIs potently synergize with paclitaxel and other microtubule-stabilizing drugs; however, the mechanistic basis underlying this synergistic interaction remains elusive. Here we show that the FTI Lonafarnib affects the microtubule cytoskeleton resulting in microtubule bundle formation, increased microtubule stabilization and acetylation, and suppression of microtubule dynamics. Notably, treatment with the combination of low doses of Lonafarnib with paclitaxel markedly enhanced tubulin acetylation (a marker of microtubule stability) as compared with either drug alone. This synergistic effect correlated with FT inhibition and was accompanied by a synergistic increase in mitotic arrest and cell death. Mechanistically, we show that the combination of Lonafarnib and paclitaxel inhibits the in vitro deacetylating activity of the only known tubulin deacetylase, histone deacetylase 6 (HDAC6). In addition, the Lonafarnib/taxane combination is synergistic only in cells lines expressing the wild-type HDAC6, but not a catalytic-mutant HDAC6, revealing that functional HDAC6 is required for the synergy of Lonafarnib with taxanes. Furthermore, tubacin, a specific HDAC6 inhibitor, synergistically enhanced tubulin acetylation in combination with paclitaxel, similar to the combination of Lonafarnib and paclitaxel. Taken together, these data suggest a relationship between FT inhibition, HDAC6 function, and cell death, providing insight into the putative molecular basis of the Lonafarnib/taxane synergistic antiproliferative combination.
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The synergistic combination of the farnesyl transferase inhibitor Lonafarnib and paclitaxel enhances tubulin acetylation and requires a functional tubulin deacetylase. Cancer Res
2005Co-Authors: Adam I Marcus, Fadlo R Khuri, Ernest Hamel, Michael C. Nivens, Tso-pang Yao, Jason Wong, Adel El-naggar, Paraskevi GiannakakouAbstract:Farnesyl transferase (FT) inhibitors (FTI) are anticancer agents developed to target oncogenic Ras proteins by inhibiting Ras farnesylation. FTIs potently synergize with paclitaxel and other microtubule-stabilizing drugs; however, the mechanistic basis underlying this synergistic interaction remains elusive. Here we show that the FTI Lonafarnib affects the microtubule cytoskeleton resulting in microtubule bundle formation, increased microtubule stabilization and acetylation, and suppression of microtubule dynamics. Notably, treatment with the combination of low doses of Lonafarnib with paclitaxel markedly enhanced tubulin acetylation (a marker of microtubule stability) as compared with either drug alone. This synergistic effect correlated with FT inhibition and was accompanied by a synergistic increase in mitotic arres
Jan H.m. Schellens - One of the best experts on this subject based on the ideXlab platform.
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A phase I study of Lonafarnib, a farnesyl transferase inhibitor in combination with herceptin plus paclitaxel in Her 2 / neu overexpressing breast cancer
Molecular Cancer Therapeutics, 2007Co-Authors: Jan H.m. Schellens, Anne-sophie Govaerts, Sandrine Marreaud, Veronique Dieras, Marja Roelvink, Ahmad Awada, Jan Bogaerts, Denis LacombeAbstract:B116 Background: Lonafarnib (SCH 66336) is a farnesyl transferase inhibitor. This phase I study assessed the safety and tolerability of Lonafarnib (L) administered in combination with herceptin (H) plus paclitaxel (P) every 21 days in Her 2/ neu metastatic breast cancer (MBC). Patients and Methods: Patients (pts), first or second line MBC, were treated with escalating doses of L administered orally twice daily in combination with H (4 mg/kg loading dose, 2 mg/kg weekly thereafter) and P (175 mg/m² except 135 mg/m² at dose level 1 (DL)) with cycles repeated every 3 weeks. Lonafarnib was administered continuously at DLs of 75, 100, 125 mg/bid and from d1-d7 and d15-21 at DL of 150 mg/bid. At least three pts were treated at each dose level, and the maximum tolerated dose (MTD) was defined as the highest DL that was not associated with an unacceptable severe toxicity (dose associated with a probability of acute Dose Limiting Toxicity (DLT) closest to 20%). Results: Twenty three pts with a median age of 49 years (range 34-68) received 185 cycles of treatment with a median duration of 6 cycles (range 1-26) and 6 pts are still on treatment. The median PS was 0 and 14 pts had prior exposure to anthracycline. Five DLs were investigated and the trial was interrupted before reaching the MTD upon the sponsor’s request. To date, nineteen pts went off protocol, 10 due to toxicity, 2 upon patient’s request, 3 upon investigator decision and 4 for PD. The adverse events for which patients went off protocol were: neutropenia (6), neuropathy (2), allergic reaction (1) and ischemia and increase QTc (1). At the highest DL (L 300 mg/d) one out of eight pts experienced DLT of grade 3 allergic reaction. The related toxicity profile (≥ 35 % of all pats at any time) was fatigue, sensory neuropathy, myalgia, diarrhea, nausea, arthralgia, skin rash, G4 neutropenia, G2 anemia, abdominal pain, vomiting, stomatitis and anorexia. Radiological responses were documented in 10 /18 pts assessable (1 CR, 9 PR), with an additional 6 SD. To date, with a median follow-up of 6.5 months, the progression free survival at 6 months is 85%. Conclusions: The toxicity profile observed was consistent with that expected for this regimen. Preliminary efficacy results are very promising. Thus, this combined treatment merits further investigation.
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a phase i study of Lonafarnib a farnesyl transferase inhibitor in combination with herceptin plus paclitaxel in her 2 neu overexpressing breast cancer
Molecular Cancer Therapeutics, 2007Co-Authors: Jan H.m. Schellens, Anne-sophie Govaerts, Sandrine Marreaud, Veronique Dieras, Marja Roelvink, Ahmad Awada, Jan Bogaerts, Denis LacombeAbstract:B116 Background: Lonafarnib (SCH 66336) is a farnesyl transferase inhibitor. This phase I study assessed the safety and tolerability of Lonafarnib (L) administered in combination with herceptin (H) plus paclitaxel (P) every 21 days in Her 2/ neu metastatic breast cancer (MBC). Patients and Methods: Patients (pts), first or second line MBC, were treated with escalating doses of L administered orally twice daily in combination with H (4 mg/kg loading dose, 2 mg/kg weekly thereafter) and P (175 mg/m² except 135 mg/m² at dose level 1 (DL)) with cycles repeated every 3 weeks. Lonafarnib was administered continuously at DLs of 75, 100, 125 mg/bid and from d1-d7 and d15-21 at DL of 150 mg/bid. At least three pts were treated at each dose level, and the maximum tolerated dose (MTD) was defined as the highest DL that was not associated with an unacceptable severe toxicity (dose associated with a probability of acute Dose Limiting Toxicity (DLT) closest to 20%). Results: Twenty three pts with a median age of 49 years (range 34-68) received 185 cycles of treatment with a median duration of 6 cycles (range 1-26) and 6 pts are still on treatment. The median PS was 0 and 14 pts had prior exposure to anthracycline. Five DLs were investigated and the trial was interrupted before reaching the MTD upon the sponsor’s request. To date, nineteen pts went off protocol, 10 due to toxicity, 2 upon patient’s request, 3 upon investigator decision and 4 for PD. The adverse events for which patients went off protocol were: neutropenia (6), neuropathy (2), allergic reaction (1) and ischemia and increase QTc (1). At the highest DL (L 300 mg/d) one out of eight pts experienced DLT of grade 3 allergic reaction. The related toxicity profile (≥ 35 % of all pats at any time) was fatigue, sensory neuropathy, myalgia, diarrhea, nausea, arthralgia, skin rash, G4 neutropenia, G2 anemia, abdominal pain, vomiting, stomatitis and anorexia. Radiological responses were documented in 10 /18 pts assessable (1 CR, 9 PR), with an additional 6 SD. To date, with a median follow-up of 6.5 months, the progression free survival at 6 months is 85%. Conclusions: The toxicity profile observed was consistent with that expected for this regimen. Preliminary efficacy results are very promising. Thus, this combined treatment merits further investigation.
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Quantitative analysis of the farnesyl transferase inhibitor Lonafarnib (Sarasar™, SCH66336) in human plasma using high‐performance liquid chromatography coupled with tandem mass spectrometry
Rapid communications in mass spectrometry : RCM, 2005Co-Authors: Natalie M. G. M. Appels, Hilde Rosing, Maria J. Van Maanen, Jan H.m. Schellens, Jos H. BeijnenAbstract:Lonafarnib is a novel anticancer drug that inhibits farnesyl transferase. To assess its pharmacokinetic properties, we developed a sensitive and quantitative assay using liquid chromatography coupled with tandem mass spectrometry for the determination of Lonafarnib levels in human plasma. Sample pretreatment consisted of the addition of an isotopically labeled internal standard and protein precipitation with acetonitrile using 100 µL plasma. Chromatographic separation was performed on an Inertsil ODS-3 analytical column (50 × 2.1 mm i.d., particle size 5 µm) with acetonitrile/water/formic acid (50:50:0.05, v/v/v) as the mobile phase, at a flow rate of 0.2 mL/min. The analytical run time was 8 min. An API365 triple quadrupole mass spectrometer was used for specific and sensitive detection. It was operated in the positive ion mode and multiple reaction monitoring was used for drug quantification. The method was validated using a concentration range of 2.5 to 2500 ng/mL Lonafarnib. Validation of the assay was performed according to the most recent FDA guidelines for bioanalytical method validation and all results were within the requirements. The described method was successfully applied to support a clinical phase I trial with Lonafarnib. Copyright © 2005 John Wiley & Sons, Ltd.
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quantitative analysis of the farnesyl transferase inhibitor Lonafarnib sarasar sch66336 in human plasma using high performance liquid chromatography coupled with tandem mass spectrometry
Rapid Communications in Mass Spectrometry, 2005Co-Authors: Natalie M. G. M. Appels, Hilde Rosing, Jos H. Beijnen, Maria J. Van Maanen, Jan H.m. SchellensAbstract:Lonafarnib is a novel anticancer drug that inhibits farnesyl transferase. To assess its pharmacokinetic properties, we developed a sensitive and quantitative assay using liquid chromatography coupled with tandem mass spectrometry for the determination of Lonafarnib levels in human plasma. Sample pretreatment consisted of the addition of an isotopically labeled internal standard and protein precipitation with acetonitrile using 100 µL plasma. Chromatographic separation was performed on an Inertsil ODS-3 analytical column (50 × 2.1 mm i.d., particle size 5 µm) with acetonitrile/water/formic acid (50:50:0.05, v/v/v) as the mobile phase, at a flow rate of 0.2 mL/min. The analytical run time was 8 min. An API365 triple quadrupole mass spectrometer was used for specific and sensitive detection. It was operated in the positive ion mode and multiple reaction monitoring was used for drug quantification. The method was validated using a concentration range of 2.5 to 2500 ng/mL Lonafarnib. Validation of the assay was performed according to the most recent FDA guidelines for bioanalytical method validation and all results were within the requirements. The described method was successfully applied to support a clinical phase I trial with Lonafarnib. Copyright © 2005 John Wiley & Sons, Ltd.
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Farnesyl transferase inhibitors impair chromosomal maintenance in cell lines and human tumors by compromising CENP-E and CENP-F function.
Molecular cancer therapeutics, 2007Co-Authors: Katherine Schafer-hales, Fadlo R Khuri, Adel K. El-naggar, Paraskevi Giannakakou, Jonathan Iaconelli, James P. Snyder, Andrew Prussia, James H. Nettles, Adam I MarcusAbstract:Farnesyl transferase inhibitors (FTI) exhibit anticancer activity as a single agent in preclinical studies and show promise in combination with other therapeutics in clinical trials. Previous studies show that FTIs arrest cancer cells in mitosis; however, the mechanism by which this occurs is unclear. Here, we observed that treatment of various cancer cell lines with the FTI Lonafarnib caused mitotic chromosomal alignment defects, leaving cells in a pseudometaphase state, whereby both aligned chromosomes and chromosomes juxtaposed to the spindle poles (termed ‘‘lagging chromosomes’’) were observed in the same cell. To determine how this occurs, we investigated the functionality of two farnesylated mitotic proteins, CENPE and CENP-F, which mediate chromosomal capture and alignment. The data show that Lonafarnib in proliferating cancer cells depletes CENP-E and CENP-F from metaphase but not prometaphase kinetochores. Loss of CENP-E and CENP-F metaphase localization triggered aberrant chromosomal maintenance, causing aligned chromosomes to be prematurely released from the spindle equator and become lagging chromosomes, resulting in a mitotic delay. Furthermore, Lonafarnib treatment reduces sister kinetochore tension and activates the BubR1 spindle checkpoint, suggesting that farnesylation of CENP-E and CENP-F is critical for their functionality in maintaining kinetochoremicrotubule interactions. Importantly, apparently similar chromosomal alignment defects were observed in head and neck tumors samples from a phase I trial with Lonafarnib, providing support that Lonafarnib disrupts chromosomal maintenance in human cancers. Lastly, to examine how farnesylation could regulate CENP-E in mediating kinetochore-microtubule attachments, we examined possible docking motifs of a farnesyl group on the outer surface of the microtubule. This analysis revealed three hydrophobic patches on the tubulin dimer for insertion of a farnesyl group, alluding to the possibility of an association between a farnesyl group and the microtubule. [Mol Cancer Ther 2007;6(4):1317 – 28]
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The Synergistic Combination of the Farnesyl Transferase Inhibitor Lonafarnib and Paclitaxel Enhances Tubulin Acetylation and Requires a Functional Tubulin Deacetylase
Cancer research, 2005Co-Authors: Adam I Marcus, Fadlo R Khuri, Jun Zhou, Aurora O'brate, Ernest Hamel, Jason Y.y. Wong, Michael C. Nivens, Adel K. El-naggar, Tso-pang Yao, Paraskevi GiannakakouAbstract:Farnesyl transferase (FT) inhibitors (FTI) are anticancer agents developed to target oncogenic Ras proteins by inhibiting Ras farnesylation. FTIs potently synergize with paclitaxel and other microtubule-stabilizing drugs; however, the mechanistic basis underlying this synergistic interaction remains elusive. Here we show that the FTI Lonafarnib affects the microtubule cytoskeleton resulting in microtubule bundle formation, increased microtubule stabilization and acetylation, and suppression of microtubule dynamics. Notably, treatment with the combination of low doses of Lonafarnib with paclitaxel markedly enhanced tubulin acetylation (a marker of microtubule stability) as compared with either drug alone. This synergistic effect correlated with FT inhibition and was accompanied by a synergistic increase in mitotic arrest and cell death. Mechanistically, we show that the combination of Lonafarnib and paclitaxel inhibits the in vitro deacetylating activity of the only known tubulin deacetylase, histone deacetylase 6 (HDAC6). In addition, the Lonafarnib/taxane combination is synergistic only in cells lines expressing the wild-type HDAC6, but not a catalytic-mutant HDAC6, revealing that functional HDAC6 is required for the synergy of Lonafarnib with taxanes. Furthermore, tubacin, a specific HDAC6 inhibitor, synergistically enhanced tubulin acetylation in combination with paclitaxel, similar to the combination of Lonafarnib and paclitaxel. Taken together, these data suggest a relationship between FT inhibition, HDAC6 function, and cell death, providing insight into the putative molecular basis of the Lonafarnib/taxane synergistic antiproliferative combination.
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The synergistic combination of the farnesyl transferase inhibitor Lonafarnib and paclitaxel enhances tubulin acetylation and requires a functional tubulin deacetylase. Cancer Res
2005Co-Authors: Adam I Marcus, Fadlo R Khuri, Ernest Hamel, Michael C. Nivens, Tso-pang Yao, Jason Wong, Adel El-naggar, Paraskevi GiannakakouAbstract:Farnesyl transferase (FT) inhibitors (FTI) are anticancer agents developed to target oncogenic Ras proteins by inhibiting Ras farnesylation. FTIs potently synergize with paclitaxel and other microtubule-stabilizing drugs; however, the mechanistic basis underlying this synergistic interaction remains elusive. Here we show that the FTI Lonafarnib affects the microtubule cytoskeleton resulting in microtubule bundle formation, increased microtubule stabilization and acetylation, and suppression of microtubule dynamics. Notably, treatment with the combination of low doses of Lonafarnib with paclitaxel markedly enhanced tubulin acetylation (a marker of microtubule stability) as compared with either drug alone. This synergistic effect correlated with FT inhibition and was accompanied by a synergistic increase in mitotic arres
