Measuring the Pharmacodynamic Effects of a Novel Hsp90 Inhibitor on HER2/neu Expression in Mice Using 89Zr-DFO-Trastuzumab
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{"title"=>"Measuring the Pharmacodynamic Effects of a Novel Hsp90 Inhibitor on HER2/neu Expression in Mice Using 89Zr-DFO-Trastuzumab", "type"=>"journal", "authors"=>[{"first_name"=>"Jason P.", "last_name"=>"Holland"}, {"first_name"=>"Eloisi", "last_name"=>"Caldas-Lopes"}, {"first_name"=>"Vadim", "last_name"=>"Divilov"}, {"first_name"=>"Valerie A.", "last_name"=>"Longo"}, {"first_name"=>"Tony", "last_name"=>"Taldone"}, {"first_name"=>"Danuta", "last_name"=>"Zatorska"}, {"first_name"=>"Gabriela", "last_name"=>"Chiosis"}, {"first_name"=>"Jason S.", "last_name"=>"Lewis"}], "year"=>2010, "source"=>"PLoS ONE", "identifiers"=>{"issn"=>"1932-6203", "doi"=>"10.1371/journal.pone.0008859", "pmid"=>"20111600"}, "id"=>"99fd1f65-cb29-3590-8213-44bdd4638a1d", "abstract"=>"BACKGROUND: The positron-emitting radionuclide (89)Zr (t(1/2) = 3.17 days) was used to prepare (89)Zr-radiolabeled trastuzumab for use as a radiotracer for characterizing HER2/neu-positive breast tumors. In addition, pharmacodynamic studies on HER2/neu expression levels in response to therapeutic doses of PU-H71 (a specific inhibitor of heat-shock protein 90 [Hsp90]) were conducted. METHODOLOGY/PRINCIPAL FINDINGS: Trastuzumab was functionalized with desferrioxamine B (DFO) and radiolabeled with [(89)Zr]Zr-oxalate at room temperature using modified literature methods. ImmunoPET and biodistribution experiments in female, athymic nu/nu mice bearing sub-cutaneous BT-474 (HER2/neu positive) and/or MDA-MB-468 (HER2/neu negative) tumor xenografts were conducted. The change in (89)Zr-DFO-trastuzumab tissue uptake in response to high- and low-specific-activity formulations and co-administration of PU-H71 was evaluated by biodistribution studies, Western blot analysis and immunoPET. (89)Zr-DFO-trastuzumab radiolabeling proceeded in high radiochemical yield and specific-activity 104.3+/-2.1 MBq/mg (2.82+/-0.05 mCi/mg of mAb). In vitro assays demonstrated >99% radiochemical purity with an immunoreactive fraction of 0.87+/-0.07. In vivo biodistribution experiments revealed high specific BT-474 uptake after 24, 48 and 72 h (64.68+/-13.06%ID/g; 71.71+/-10.35%ID/g and 85.18+/-11.10%ID/g, respectively) with retention of activity for over 120 h. Pre-treatment with PU-H71 was followed by biodistribution studies and immunoPET of (89)Zr-DFO-trastuzumab. Expression levels of HER2/neu were modulated during the first 24 and 48 h post-administration (29.75+/-4.43%ID/g and 41.42+/-3.64%ID/g, respectively). By 72 h radiotracer uptake (73.64+/-12.17%ID/g) and Western blot analysis demonstrated that HER2/neu expression recovered to baseline levels. CONCLUSIONS/SIGNIFICANCE: The results indicate that (89)Zr-DFO-trastuzumab provides quantitative and highly-specific delineation of HER2/neu positive tumors, and has potential to be used to measure the efficacy of long-term treatment with Hsp90 inhibitors, like PU-H71, which display extended pharmacodynamic profiles.", "link"=>"http://www.mendeley.com/research/measuring-pharmacodynamic-effects-novel-hsp90-inhibitor-her2neu-expression-mice-using-89zrdfotrastuz", "reader_count"=>5, "reader_count_by_academic_status"=>{"Researcher"=>2, "Student > Ph. D. Student"=>3}, "reader_count_by_user_role"=>{"Researcher"=>2, "Student > Ph. D. Student"=>3}, "reader_count_by_subject_area"=>{"Agricultural and Biological Sciences"=>2, "Chemistry"=>3}, "reader_count_by_subdiscipline"=>{"Chemistry"=>{"Chemistry"=>3}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>2}}, "reader_count_by_country"=>{"Canada"=>2}, "group_count"=>0}

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  • {"files"=>["https://ndownloader.figshare.com/files/866870"], "description"=>"<p>Pharmacodynamic studies on protein expression levels in BT-474 tumor tissue samples obtained at 12, 24, 48, 72 and 96 h after PU-H71 treatment.</p>", "links"=>[], "tags"=>["studies", "levels", "bt-474", "samples", "72", "96", "pu-h71"], "article_id"=>537312, "categories"=>["Medicine", "Plant Biology", "Chemistry"], "users"=>["Jason P. Holland", "Eloisi Caldas-Lopes", "Vadim Divilov", "Valerie A. Longo", "Tony Taldone", "Danuta Zatorska", "Gabriela Chiosis", "Jason S. Lewis"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0008859.g004", "stats"=>{"downloads"=>3, "page_views"=>10, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Pharmacodynamic_studies_on_protein_expression_levels_in_BT_474_tumor_tissue_samples_obtained_at_12_24_48_72_and_96_h_after_PU_H71_treatment_/537312", "title"=>"Pharmacodynamic studies on protein expression levels in BT-474 tumor tissue samples obtained at 12, 24, 48, 72 and 96 h after PU-H71 treatment.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-01-25 02:01:52"}
  • {"files"=>["https://ndownloader.figshare.com/files/867159"], "description"=>"<p>Mean and maximum T/M ratios obtained from VOI analysis are presented (<a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0008859#pone.0008859.s009\" target=\"_blank\">Table S3</a>). For the control animal, the two coronal PET slices lie through the center of the HER2/<i>neu</i> positive and negative tumors.</p>", "links"=>[], "tags"=>["immunopet", "images", "pu-h71", "treated", "mice", "bearing", "bt-474", "mda-mb-468", "tumors", "recorded", "24"], "article_id"=>537600, "categories"=>["Medicine", "Plant Biology", "Chemistry"], "users"=>["Jason P. Holland", "Eloisi Caldas-Lopes", "Vadim Divilov", "Valerie A. Longo", "Tony Taldone", "Danuta Zatorska", "Gabriela Chiosis", "Jason S. Lewis"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0008859.g007", "stats"=>{"downloads"=>2, "page_views"=>20, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Coronal_immunoPET_images_of_control_left_and_PU_H71_right_treated_mice_bearing_s_c_BT_474_and_MDA_MB_468_tumors_recorded_at_24_h_post_i_v_administration_of_89_Zr_DFO_trastuzumab_/537600", "title"=>"Coronal immunoPET images of control (left) and PU-H71 (right) treated mice bearing s.c. BT-474 and MDA-MB-468 tumors recorded at 24 h post-i.v. administration of <sup>89</sup>Zr-DFO-trastuzumab.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-01-25 02:06:40"}
  • {"files"=>["https://ndownloader.figshare.com/files/866786"], "description"=>"<p>Bar charts showing selected tissue biodistribution data (%ID/g) for (A) uptake of high and low specific-activity formulations of <sup>89</sup>Zr-DFO-trastuzumab in BT-474 tumor-bearing mice, and (B) <sup>89</sup>Zr-DFO-trastuzumab uptake in control (vehicle-treated) and PU-H71 treated animals at 12, 24, 48 and 72 h post-i.v. administration of <sup>89</sup>Zr-DFO-trastuzumab (0.55–0.74 MBq, 5–7 µg of mAb, in 200 µL 0.9% sterile saline).</p>", "links"=>[], "tags"=>["charts", "biodistribution", "uptake", "specific-activity", "formulations", "bt-474", "tumor-bearing", "pu-h71", "treated", "animals", "48", "72", "200", "sterile"], "article_id"=>537219, "categories"=>["Medicine", "Plant Biology", "Chemistry"], "users"=>["Jason P. Holland", "Eloisi Caldas-Lopes", "Vadim Divilov", "Valerie A. Longo", "Tony Taldone", "Danuta Zatorska", "Gabriela Chiosis", "Jason S. Lewis"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0008859.g003", "stats"=>{"downloads"=>2, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Bar_charts_showing_selected_tissue_biodistribution_data_ID_g_for_A_uptake_of_high_and_low_specific_activity_formulations_of_89_Zr_DFO_trastuzumab_in_BT_474_tumor_bearing_mice_and_B_89_Zr_DFO_trastuzumab_uptake_in_control_vehicle_treated_and_PU_H71_treate/537219", "title"=>"Bar charts showing selected tissue biodistribution data (%ID/g) for (A) uptake of high and low specific-activity formulations of <sup>89</sup>Zr-DFO-trastuzumab in BT-474 tumor-bearing mice, and (B) <sup>89</sup>Zr-DFO-trastuzumab uptake in control (vehicle-treated) and PU-H71 treated animals at 12, 24, 48 and 72 h post-i.v. administration of <sup>89</sup>Zr-DFO-trastuzumab (0.55–0.74 MBq, 5–7 µg of mAb, in 200 µL 0.9% sterile saline).", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-01-25 02:00:19"}
  • {"files"=>["https://ndownloader.figshare.com/files/429908", "https://ndownloader.figshare.com/files/430011", "https://ndownloader.figshare.com/files/430036", "https://ndownloader.figshare.com/files/430057", "https://ndownloader.figshare.com/files/430075", "https://ndownloader.figshare.com/files/430100", "https://ndownloader.figshare.com/files/430116", "https://ndownloader.figshare.com/files/430168", "https://ndownloader.figshare.com/files/430201", "https://ndownloader.figshare.com/files/430232"], "description"=>"<div><h3>Background</h3><p>The positron-emitting radionuclide <sup>89</sup>Zr (<em>t</em><sub>1/2</sub> = 3.17 days) was used to prepare <sup>89</sup>Zr-radiolabeled trastuzumab for use as a radiotracer for characterizing HER2/<em>neu</em>-positive breast tumors. In addition, pharmacodynamic studies on HER2/<em>neu</em> expression levels in response to therapeutic doses of PU-H71 (a specific inhibitor of heat-shock protein 90 [Hsp90]) were conducted.</p><h3>Methodology/Principal Findings</h3><p>Trastuzumab was functionalized with desferrioxamine B (DFO) and radiolabeled with [<sup>89</sup>Zr]Zr-oxalate at room temperature using modified literature methods. ImmunoPET and biodistribution experiments in female, athymic <em>nu</em>/<em>nu</em> mice bearing sub-cutaneous BT-474 (HER2/<em>neu</em> positive) and/or MDA-MB-468 (HER2/<em>neu</em> negative) tumor xenografts were conducted. The change in <sup>89</sup>Zr-DFO-trastuzumab tissue uptake in response to high- and low-specific-activity formulations and co-administration of PU-H71 was evaluated by biodistribution studies, Western blot analysis and immunoPET. <sup>89</sup>Zr-DFO-trastuzumab radiolabeling proceeded in high radiochemical yield and specific-activity 104.3±2.1 MBq/mg (2.82±0.05 mCi/mg of mAb). <em>In vitro</em> assays demonstrated >99% radiochemical purity with an immunoreactive fraction of 0.87±0.07. <em>In vivo</em> biodistribution experiments revealed high specific BT-474 uptake after 24, 48 and 72 h (64.68±13.06%ID/g; 71.71±10.35%ID/g and 85.18±11.10%ID/g, respectively) with retention of activity for over 120 h. Pre-treatment with PU-H71 was followed by biodistribution studies and immunoPET of <sup>89</sup>Zr-DFO-trastuzumab. Expression levels of HER2/<em>neu</em> were modulated during the first 24 and 48 h post-administration (29.75±4.43%ID/g and 41.42±3.64%ID/g, respectively). By 72 h radiotracer uptake (73.64±12.17%ID/g) and Western blot analysis demonstrated that HER2/<em>neu</em> expression recovered to baseline levels.</p><h3>Conclusions/Significance</h3><p>The results indicate that <sup>89</sup>Zr-DFO-trastuzumab provides quantitative and highly-specific delineation of HER2/<em>neu</em> positive tumors, and has potential to be used to measure the efficacy of long-term treatment with Hsp90 inhibitors, like PU-H71, which display extended pharmacodynamic profiles.</p></div>", "links"=>[], "tags"=>["measuring", "pharmacodynamic", "effects", "hsp90", "inhibitor", "mice"], "article_id"=>144870, "categories"=>["Medicine", "Cell Biology", "Chemistry"], "users"=>["Jason P. Holland", "Eloisi Caldas-Lopes", "Vadim Divilov", "Valerie A. Longo", "Tony Taldone", "Danuta Zatorska", "Gabriela Chiosis", "Jason S. Lewis"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0008859.s001", "https://dx.doi.org/10.1371/journal.pone.0008859.s002", "https://dx.doi.org/10.1371/journal.pone.0008859.s003", "https://dx.doi.org/10.1371/journal.pone.0008859.s004", "https://dx.doi.org/10.1371/journal.pone.0008859.s005", "https://dx.doi.org/10.1371/journal.pone.0008859.s006", "https://dx.doi.org/10.1371/journal.pone.0008859.s007", "https://dx.doi.org/10.1371/journal.pone.0008859.s008", "https://dx.doi.org/10.1371/journal.pone.0008859.s009", "https://dx.doi.org/10.1371/journal.pone.0008859.s010"], "stats"=>{"downloads"=>21, "page_views"=>15, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Measuring_the_Pharmacodynamic_Effects_of_a_Novel_Hsp90_Inhibitor_on_HER2_neu_Expression_in_Mice_Using_89_Zr_DFO_Trastuzumab/144870", "title"=>"Measuring the Pharmacodynamic Effects of a Novel Hsp90 Inhibitor on HER2/<em>neu</em> Expression in Mice Using <sup>89</sup>Zr-DFO-Trastuzumab", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2010-01-25 01:21:10"}
  • {"files"=>["https://ndownloader.figshare.com/files/866609"], "description"=>"<p>Plot of the (total/bound) activity <i>versus</i> (1/[normalized cell concentration]), used to calculate the immunoreactivity fraction of <sup>89</sup>Zr-DFO-trastuzumab in BT-474 (HER2/<i>neu</i> positive) cells by extrapolation to infinite antigen excess (1/<i>y</i>-intercept).</p>", "links"=>[], "tags"=>["immunoreactivity", "bt-474", "cells", "extrapolation", "infinite", "antigen", "excess"], "article_id"=>537059, "categories"=>["Medicine", "Plant Biology", "Chemistry"], "users"=>["Jason P. Holland", "Eloisi Caldas-Lopes", "Vadim Divilov", "Valerie A. Longo", "Tony Taldone", "Danuta Zatorska", "Gabriela Chiosis", "Jason S. Lewis"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0008859.g001", "stats"=>{"downloads"=>10, "page_views"=>40, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Plot_of_the_total_bound_activity_versus_1_normalized_cell_concentration_used_to_calculate_the_immunoreactivity_fraction_of_89_Zr_DFO_trastuzumab_in_BT_474_HER2_neu_positive_cells_by_extrapolation_to_infinite_antigen_excess_1_y_intercept_/537059", "title"=>"Plot of the (total/bound) activity <i>versus</i> (1/[normalized cell concentration]), used to calculate the immunoreactivity fraction of <sup>89</sup>Zr-DFO-trastuzumab in BT-474 (HER2/<i>neu</i> positive) cells by extrapolation to infinite antigen excess (1/<i>y</i>-intercept).", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-01-25 01:57:39"}
  • {"files"=>["https://ndownloader.figshare.com/files/867232"], "description"=>"<p><sup>a</sup>Complete biodistribution data are presented in the supporting information (<a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0008859#pone.0008859.s007\" target=\"_blank\">Table S1</a>).</p><p><sup>b</sup>The data are expressed as the mean %ID/g ± one standard deviation (S.D.).</p>", "links"=>[], "tags"=>["administered", "tail-vein", "injection", "athymic", "mice", "bearing", "bt-474", "tumors"], "article_id"=>537680, "categories"=>["Medicine", "Plant Biology", "Chemistry"], "users"=>["Jason P. Holland", "Eloisi Caldas-Lopes", "Vadim Divilov", "Valerie A. Longo", "Tony Taldone", "Danuta Zatorska", "Gabriela Chiosis", "Jason S. Lewis"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0008859.t001", "stats"=>{"downloads"=>0, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Biodistribution_data_of_89_Zr_DFO_trastuzumab_versus_time_h_administered_by_i_v_tail_vein_injection_to_female_athymic_nu_nu_mice_bearing_s_c_BT_474_tumors_90_150_mm_3_a_b_/537680", "title"=>"Biodistribution data of <sup>89</sup>Zr-DFO-trastuzumab <i>versus</i> time/h, administered by i.v. tail-vein injection to female, athymic <i>nu</i>/<i>nu</i> mice bearing s.c. BT-474 tumors (90–150 mm<sup>3</sup>).<sup>a,b</sup>", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2010-01-25 02:08:00"}
  • {"files"=>["https://ndownloader.figshare.com/files/866960"], "description"=>"<p>The transverse (top) and coronal (bottom) planar images intersect the center of the tumors.</p>", "links"=>[], "tags"=>["images", "200", "sterile", "recorded", "bt-474", "mda-mb-468", "tumor-bearing", "mice"], "article_id"=>537404, "categories"=>["Medicine", "Plant Biology", "Chemistry"], "users"=>["Jason P. Holland", "Eloisi Caldas-Lopes", "Vadim Divilov", "Valerie A. Longo", "Tony Taldone", "Danuta Zatorska", "Gabriela Chiosis", "Jason S. Lewis"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0008859.g005", "stats"=>{"downloads"=>2, "page_views"=>17, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_ImmunoPET_images_of_89_Zr_DFO_trastuzumab_8_50_8211_9_25_MBq_80_8211_90_181_g_of_mAb_in_200_181_L_0_9_sterile_saline_recorded_in_A_BT_474_left_shoulder_and_B_MDA_MB_468_right_flank_tumor_bearing_mice_between_1_8211_120_h_post_injection_/537404", "title"=>"ImmunoPET images of <sup>89</sup>Zr-DFO-trastuzumab (8.50–9.25 MBq, 80–90 µg of mAb, in 200 µL 0.9% sterile saline) recorded in (A) BT-474 (left shoulder) and (B) MDA-MB-468 (right flank) tumor-bearing mice between 1–120 h post-injection.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-01-25 02:03:24"}
  • {"files"=>["https://ndownloader.figshare.com/files/866692"], "description"=>"<p>DMSO vehicle treated experiments and β-actin are include as controls. Proteins investigated include: HER2/<i>neu</i>; Akt; phosphorylated Akt (P-Akt); the apoptosis marker, cleaved poly (ADP-ribose) polymerase (cPARP); RAF1; Hsp90; Hsp70; and β-actin as a protein loading control.</p>", "links"=>[], "tags"=>["blots", "levels", "pu-h71"], "article_id"=>537145, "categories"=>["Medicine", "Plant Biology", "Chemistry"], "users"=>["Jason P. Holland", "Eloisi Caldas-Lopes", "Vadim Divilov", "Valerie A. Longo", "Tony Taldone", "Danuta Zatorska", "Gabriela Chiosis", "Jason S. Lewis"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0008859.g002", "stats"=>{"downloads"=>0, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_In_vitro_Western_blots_showing_the_change_in_protein_expression_levels_in_response_to_treatment_with_PU_H71_at_0_01_1_M_concentrations_/537145", "title"=>"<i>In vitro</i> Western blots showing the change in protein expression levels in response to treatment with PU-H71 at 0.01–1 µM concentrations.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-01-25 01:59:05"}
  • {"files"=>["https://ndownloader.figshare.com/files/867055"], "description"=>"<p>Time-activity curves derived by region-of-interest analysis of the immunoPET images showing the mean %ID/g tissue uptake <i>versus</i> time/h, for control and PU-H71-treated mice bearing both BT-474 and MDA-MB-468 tumors.</p>", "links"=>[], "tags"=>["curves", "derived", "region-of-interest", "immunopet", "images", "uptake", "pu-h71-treated", "mice", "bearing", "bt-474", "mda-mb-468"], "article_id"=>537496, "categories"=>["Medicine", "Plant Biology", "Chemistry"], "users"=>["Jason P. Holland", "Eloisi Caldas-Lopes", "Vadim Divilov", "Valerie A. Longo", "Tony Taldone", "Danuta Zatorska", "Gabriela Chiosis", "Jason S. Lewis"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0008859.g006", "stats"=>{"downloads"=>0, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Time_activity_curves_derived_by_region_of_interest_analysis_of_the_immunoPET_images_showing_the_mean_ID_g_tissue_uptake_versus_time_h_for_control_and_PU_H71_treated_mice_bearing_both_BT_474_and_MDA_MB_468_tumors_/537496", "title"=>"Time-activity curves derived by region-of-interest analysis of the immunoPET images showing the mean %ID/g tissue uptake <i>versus</i> time/h, for control and PU-H71-treated mice bearing both BT-474 and MDA-MB-468 tumors.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2010-01-25 02:04:56"}

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