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n2:pmcid: PMC0
bibo:doi: 10.1186%2F1471-2407-10-397
n7:contains: _:vb8363642 _:vb8363657 _:vb8363660 _:vb8363664 _:vb8363689

Subject Item: _:vb8363642
rdf:type: n7:Section
dc:title: results
n7:contains: _:vb8363644 _:vb8363645 _:vb8363646 _:vb8363647 _:vb8363643 _:vb8363656 _:vb8363652 _:vb8363653 _:vb8363654 _:vb8363655 _:vb8363648 _:vb8363649 _:vb8363650 _:vb8363651

Subject Item: _:vb8363643
rdf:type: n2:Context
rdf:value: GU81 (Figure 1A) is a derivative of the VEGFR2 antagonist GU40C4 [>>12<<]. We first characterized the ability of GU81 to compete with GU40C4 for binding to both VEGFR1 and VEGFR2 (Figure 1B).
n2:mentions: n3:18386897

Subject Item: _:vb8363644
rdf:type: n2:Context
rdf:value: The measured binding constant for the GU81:VEGFR2 interaction (KD) was 12 nM, a 3-fold improvement over the original GU40C4 [>>12<<].
n2:mentions: n3:18386897

Subject Item: _:vb8363645
rdf:type: n2:Context
rdf:value: To validate the functional activity of the GU81, we conducted a VEGFR2 autophosphorylation assay [>>12<<]. In brief, PAE-KDR cells were grown, stimulated with VEGF and treated with increasing concentrations of GU81.
n2:mentions: n3:18386897

Subject Item: _:vb8363646
rdf:type: n2:Context
rdf:value: This is a 2-fold improvement over the parent compound GU40C4, which exhibits an IC50 value of approximately 1 μM [>>12<<]. For this reason, it is expected that GU81 is a more potent inhibitor of endothelial cell proliferation when compared to GU40C4, which inhibits VEGF-induced endothelial cell proliferation at a concentration of 1 μM [12].
n2:mentions: n3:18386897

Subject Item: _:vb8363647
rdf:type: n2:Context
rdf:value: For this reason, it is expected that GU81 is a more potent inhibitor of endothelial cell proliferation when compared to GU40C4, which inhibits VEGF-induced endothelial cell proliferation at a concentration of 1 μM [>>12<<].
n2:mentions: n3:18386897

Subject Item: _:vb8363648
rdf:type: n2:Context
rdf:value: Perilipin coats lipid droplets in adipocytes and protects them against the body's natural lipases [>>18<<]. Adiponectin is secreted exclusively from adipocytes into the bloodstream where it regulates a number of metabolic processes including glucose regulation and fatty acid catabolism [19,20]. There were significantly higher levels of
n2:mentions: n3:2040638

Subject Item: _:vb8363649
rdf:type: n2:Context
rdf:value: Adiponectin is secreted exclusively from adipocytes into the bloodstream where it regulates a number of metabolic processes including glucose regulation and fatty acid catabolism [>>19<<,20]. There were significantly higher levels of perilipin in tumors from GU81 + doxorubicin treated animals when compared to tumors from doxorubicin alone treated mice (p ≤ 0.01, 1-way ANOVA) (Figure 4B). Similar results were seen when
n2:mentions: n3:12611609

Subject Item: _:vb8363650
rdf:type: n2:Context
rdf:value: Adiponectin is secreted exclusively from adipocytes into the bloodstream where it regulates a number of metabolic processes including glucose regulation and fatty acid catabolism [19,>>20<<]. There were significantly higher levels of perilipin in tumors from GU81 + doxorubicin treated animals when compared to tumors from doxorubicin alone treated mice (p ≤ 0.01, 1-way ANOVA) (Figure 4B). Similar results were seen when
n2:mentions: n3:12436346

Subject Item: _:vb8363651
rdf:type: n2:Context
rdf:value: Similar results were seen when immunohistochemistry was performed for adiponectin (Figure 4C) [>>19<<,21].
n2:mentions: n3:12611609

Subject Item: _:vb8363652
rdf:type: n2:Context
rdf:value: Similar results were seen when immunohistochemistry was performed for adiponectin (Figure 4C) [19,>>21<<].
n2:mentions: n3:19258676

Subject Item: _:vb8363653
rdf:type: n2:Context
rdf:value: Met-1 cells, which are a highly metastatic cell line derived from a MMTV-PyMT primary tumor [>>22<<], were treated in the presence or absence of 2.5 μM GU81 for 24, 48, and 72 hours.
n2:mentions: n3:16132578

Subject Item: _:vb8363654
rdf:type: n2:Context
rdf:value: Macrophage infiltration into tumors is known to be influenced by VEGF [>>9<<,10,23]; therefore, we examined macrophage infiltration following therapy using the general macrophage marker F4/80.
n2:mentions: n3:19567820

Subject Item: _:vb8363655
rdf:type: n2:Context
rdf:value: Macrophage infiltration into tumors is known to be influenced by VEGF [9,>>10<<,23]; therefore, we examined macrophage infiltration following therapy using the general macrophage marker F4/80.
n2:mentions: n3:19888452

Subject Item: _:vb8363656
rdf:type: n2:Context
rdf:value: Macrophage infiltration into tumors is known to be influenced by VEGF [9,10,>>23<<]; therefore, we examined macrophage infiltration following therapy using the general macrophage marker F4/80.
n2:mentions: n3:18519694

Subject Item: _:vb8363657
rdf:type: n7:Section
dc:title: conclusions
n7:contains: _:vb8363658 _:vb8363659

Subject Item: _:vb8363658
rdf:type: n2:Context
rdf:value: Furthermore, peptoids have high serum-stability [>>13<<], are non-immunogenic [34], and are cell permeable [35], thus making them good candidates for use in drug discovery.
n2:mentions: n3:1409642

Subject Item: _:vb8363659
rdf:type: n2:Context
rdf:value: Furthermore, peptoids have high serum-stability [13], are non-immunogenic [34], and are cell permeable [>>35<<], thus making them good candidates for use in drug discovery.
n2:mentions: n3:17283989

Subject Item: _:vb8363660
rdf:type: n7:Section
dc:title: methods
n7:contains: _:vb8363661 _:vb8363662 _:vb8363663

Subject Item: _:vb8363661
rdf:type: n2:Context
rdf:value: GU81 was developed based on the identified 'minimum pharamacophore' [>>15<<] of GU40C4 and the complete development strategy will soon be published elsewhere.
n2:mentions: n3:18653335

Subject Item: _:vb8363662
rdf:type: n2:Context
rdf:value: Primary antibodies were used at a final concentration of 5-10 μg/ml and include: rabbit anti-perilipin [>>16<<], rabbit anti-adiponectin [17], rabbit anti-phospho-histone-3 (Ser10) (Upstate, Lake Placid, NY), rabbit anti-cleaved caspase-3 (Asp 175) (Cell Signaling), rat anti-endomucin (Santa Cruz Biotechnology, Inc., Santa Cruz, CA), chicken
n2:mentions: n3:9733764

Subject Item: _:vb8363663
rdf:type: n2:Context
rdf:value: Primary antibodies were used at a final concentration of 5-10 μg/ml and include: rabbit anti-perilipin [16], rabbit anti-adiponectin [>>17<<], rabbit anti-phospho-histone-3 (Ser10) (Upstate, Lake Placid, NY), rabbit anti-cleaved caspase-3 (Asp 175) (Cell Signaling), rat anti-endomucin (Santa Cruz Biotechnology, Inc., Santa Cruz, CA), chicken anti-VEGF (Abcam, Cambridge, MA),
n2:mentions: n3:7592907

Subject Item: _:vb8363664
rdf:type: n7:Section
dc:title: discussion
n7:contains: _:vb8363684 _:vb8363685 _:vb8363686 _:vb8363687 _:vb8363680 _:vb8363681 _:vb8363682 _:vb8363683 _:vb8363688 _:vb8363668 _:vb8363669 _:vb8363670 _:vb8363671 _:vb8363665 _:vb8363666 _:vb8363667 _:vb8363676 _:vb8363677 _:vb8363678 _:vb8363679 _:vb8363672 _:vb8363673 _:vb8363674 _:vb8363675

Subject Item: _:vb8363665
rdf:type: n2:Context
rdf:value: We tested the therapeutic efficacy of GU81, both alone and in combination with doxorubicin in the extensively characterized spontaneous and aggressive MMTV-PyMT model of breast cancer [>>14<<]. While GU81 had little therapeutic efficacy when used alone, animals treated with the combination of GU81 and doxorubicin had decreased tumor burden (Figure 2A), significantly reduced tumor invasion (Figure 3), increased tumor fat
n2:mentions: n3:14578209

Subject Item: _:vb8363666
rdf:type: n2:Context
rdf:value: We began therapy when mice reached 6 weeks of age, and at this time most of the mice harbored primary neoplasia that developed to the hyperplastic stage [>>14<<,24]. In this case, the combination of GU81 + doxorubicin was able to delay tumor progression and prevent transition from a premalignant to an invasive phenotype.
n2:mentions: n3:14578209

Subject Item: _:vb8363667
rdf:type: n2:Context
rdf:value: We began therapy when mice reached 6 weeks of age, and at this time most of the mice harbored primary neoplasia that developed to the hyperplastic stage [14,>>24<<]. In this case, the combination of GU81 + doxorubicin was able to delay tumor progression and prevent transition from a premalignant to an invasive phenotype.
n2:mentions: n3:11257139

Subject Item: _:vb8363668
rdf:type: n2:Context
rdf:value: Tumor blood vessels are dilated, leaky, and inefficient at delivering both oxygen and chemotherapeutic agents to the tumor [reviewed in [>>25<<]]. Vessel dilation is decreased following treatment with GU81, which leads us to the hypothesis that GU81 may be effectively normalizing the vasculature, decreasing hypoxia, and increasing doxorubicin delivery into the tumor.
n2:mentions: n3:16301831

Subject Item: _:vb8363669
rdf:type: n2:Context
rdf:value: Interestingly, GU81 does not demonstrate in vivo efficacy as a single agent in the MMTV-PyMT model of breast cancer [>>10<<]. This is consistent with our previous studies in the MMTV-PyMT model [10] and human data, which has shown that anti-VEGF therapy provides little clinical benefit as a single agent in breast cancer [26].
n2:mentions: n3:19888452

Subject Item: _:vb8363670
rdf:type: n2:Context
rdf:value: This is consistent with our previous studies in the MMTV-PyMT model [>>10<<] and human data, which has shown that anti-VEGF therapy provides little clinical benefit as a single agent in breast cancer [26].
n2:mentions: n3:19888452

Subject Item: _:vb8363671
rdf:type: n2:Context
rdf:value: This is consistent with our previous studies in the MMTV-PyMT model [10] and human data, which has shown that anti-VEGF therapy provides little clinical benefit as a single agent in breast cancer [>>26<<]. In contrast, GU40C4, the parent compound, demonstrated single agent efficacy in the A673 Ewings' sarcoma xenograft model [12]. GU81, however, does demonstrate in vivo efficacy as a single agent in the 4T1 syngenic breast cancer model,
n2:mentions: n3:14613032

Subject Item: _:vb8363672
rdf:type: n2:Context
rdf:value: In contrast, GU40C4, the parent compound, demonstrated single agent efficacy in the A673 Ewings' sarcoma xenograft model [>>12<<]. GU81, however, does demonstrate in vivo efficacy as a single agent in the 4T1 syngenic breast cancer model, where it effectively reduces tumor size and MVD [10]. There are several possible explanations for the variation in response to
n2:mentions: n3:18386897

Subject Item: _:vb8363673
rdf:type: n2:Context
rdf:value: GU81, however, does demonstrate in vivo efficacy as a single agent in the 4T1 syngenic breast cancer model, where it effectively reduces tumor size and MVD [>>10<<]. There are several possible explanations for the variation in response to GU40C4 and GU81. Most notable is the difference in tumor model systems. The MMTV-PyMT model is a spontaneous model that develops in the mammary fat pad, which is
n2:mentions: n3:19888452

Subject Item: _:vb8363674
rdf:type: n2:Context
rdf:value: While the A673 model is a subcutaneous xenograft model that is highly dependent upon VEGF activity [>>27<<], such that even low doses of anti-VEGF agents have a striking effect on tumor growth [28].
n2:mentions: n3:16278208

Subject Item: _:vb8363675
rdf:type: n2:Context
rdf:value: While the A673 model is a subcutaneous xenograft model that is highly dependent upon VEGF activity [27], such that even low doses of anti-VEGF agents have a striking effect on tumor growth [>>28<<]. The 4T1 model is a syngeneic, highly metastatic inflammatory breast cancer model. Interestingly, recent work has identified VEGF as an autocrine survival factor for these cells under hypoxic conditions, which may explain the efficacy of
n2:mentions: n3:11016638

Subject Item: _:vb8363676
rdf:type: n2:Context
rdf:value: Interestingly, recent work has identified VEGF as an autocrine survival factor for these cells under hypoxic conditions, which may explain the efficacy of GU81 as a single agent in this model [>>29<<]. It is possible that a higher dose given for a longer period of time would be more effective at reducing microvessel density in MMTV-PyMT tumors. Furthermore, it is important to highlight that treatment with GU81 alone increased tumor
n2:mentions: n3:18097541

Subject Item: _:vb8363677
rdf:type: n2:Context
rdf:value: Macrophage infiltration is associated with poor prognosis in a number of different tumor types, including breast cancer [>>30<<,31]. After establishing that VEGF levels were increased following treatment with GU81 alone (Figure 6B), we decided to investigate what effect this increase has on macrophage infiltration, given that VEGF stimulates macrophage chemotaxis
n2:mentions: n3:12463738

Subject Item: _:vb8363678
rdf:type: n2:Context
rdf:value: Macrophage infiltration is associated with poor prognosis in a number of different tumor types, including breast cancer [30,>>31<<]. After establishing that VEGF levels were increased following treatment with GU81 alone (Figure 6B), we decided to investigate what effect this increase has on macrophage infiltration, given that VEGF stimulates macrophage chemotaxis
n2:mentions: n3:8840975

Subject Item: _:vb8363679
rdf:type: n2:Context
rdf:value: GU81 increases macrophage infiltration as a single-agent [>>10<<], however, this effect is abrogated when GU81 combined with doxorubicin (Figure 6D).
n2:mentions: n3:19888452

Subject Item: _:vb8363680
rdf:type: n2:Context
rdf:value: This increase in macrophage infiltration is puzzling as we and others have shown that anti-VEGF therapy can reduce macrophage infiltration in a number of pre-clinical models [>>9<<,10,23,32,33].
n2:mentions: n3:19567820

Subject Item: _:vb8363681
rdf:type: n2:Context
rdf:value: This increase in macrophage infiltration is puzzling as we and others have shown that anti-VEGF therapy can reduce macrophage infiltration in a number of pre-clinical models [9,>>10<<,23,32,33].
n2:mentions: n3:19888452

Subject Item: _:vb8363682
rdf:type: n2:Context
rdf:value: This increase in macrophage infiltration is puzzling as we and others have shown that anti-VEGF therapy can reduce macrophage infiltration in a number of pre-clinical models [9,10,>>23<<,32,33]. Additionally, we show that macrophages harvested from a tumor-bearing animal express both VEGFR1 and VEGFR2, whereas those harvested from non-tumor bearing mice are only VEGFR1+ [9,23]. When VEGFR2 is expressed, it becomes the
n2:mentions: n3:18519694

Subject Item: _:vb8363683
rdf:type: n2:Context
rdf:value: This increase in macrophage infiltration is puzzling as we and others have shown that anti-VEGF therapy can reduce macrophage infiltration in a number of pre-clinical models [9,10,23,>>32<<,33]. Additionally, we show that macrophages harvested from a tumor-bearing animal express both VEGFR1 and VEGFR2, whereas those harvested from non-tumor bearing mice are only VEGFR1+ [9,23]. When VEGFR2 is expressed, it becomes the
n2:mentions: n3:17019708

Subject Item: _:vb8363684
rdf:type: n2:Context
rdf:value: This increase in macrophage infiltration is puzzling as we and others have shown that anti-VEGF therapy can reduce macrophage infiltration in a number of pre-clinical models [9,10,23,32,>>33<<]. Additionally, we show that macrophages harvested from a tumor-bearing animal express both VEGFR1 and VEGFR2, whereas those harvested from non-tumor bearing mice are only VEGFR1+ [9,23]. When VEGFR2 is expressed, it becomes the dominant
n2:mentions: n3:17597103

Subject Item: _:vb8363685
rdf:type: n2:Context
rdf:value: Additionally, we show that macrophages harvested from a tumor-bearing animal express both VEGFR1 and VEGFR2, whereas those harvested from non-tumor bearing mice are only VEGFR1+ [>>9<<,23]. When VEGFR2 is expressed, it becomes the dominant receptor driving VEGF-induced chemotaxis and specific blockade of the VEGF:VEGFR2 interaction is sufficient to inhibit chemotaxis [9,23]. The most plausible explanation for the
n2:mentions: n3:19567820

Subject Item: _:vb8363686
rdf:type: n2:Context
rdf:value: Additionally, we show that macrophages harvested from a tumor-bearing animal express both VEGFR1 and VEGFR2, whereas those harvested from non-tumor bearing mice are only VEGFR1+ [9,>>23<<]. When VEGFR2 is expressed, it becomes the dominant receptor driving VEGF-induced chemotaxis and specific blockade of the VEGF:VEGFR2 interaction is sufficient to inhibit chemotaxis [9,23]. The most plausible explanation for the observed
n2:mentions: n3:18519694

Subject Item: _:vb8363687
rdf:type: n2:Context
rdf:value: When VEGFR2 is expressed, it becomes the dominant receptor driving VEGF-induced chemotaxis and specific blockade of the VEGF:VEGFR2 interaction is sufficient to inhibit chemotaxis [>>9<<,23]. The most plausible explanation for the observed increase in macrophage infiltration may be attributed to the detected increase in VEGF expression and we have not ruled out the possibility that GU81 may reduce macrophage infiltration,
n2:mentions: n3:19567820

Subject Item: _:vb8363688
rdf:type: n2:Context
rdf:value: When VEGFR2 is expressed, it becomes the dominant receptor driving VEGF-induced chemotaxis and specific blockade of the VEGF:VEGFR2 interaction is sufficient to inhibit chemotaxis [9,>>23<<]. The most plausible explanation for the observed increase in macrophage infiltration may be attributed to the detected increase in VEGF expression and we have not ruled out the possibility that GU81 may reduce macrophage infiltration, if
n2:mentions: n3:18519694

Subject Item: _:vb8363689
rdf:type: n7:Section
dc:title: background
n7:contains: _:vb8363690 _:vb8363691 _:vb8363692 _:vb8363693 _:vb8363694 _:vb8363695 _:vb8363696 _:vb8363697 _:vb8363698 _:vb8363699 _:vb8363700 _:vb8363701

Subject Item: _:vb8363690
rdf:type: n2:Context
rdf:value: Angiogenesis, the development of new blood vessels from existing vessels, is required for tumor progression and metastasis [>>2<<]. For this reason, tumor angiogenesis has become an important target for cancer therapy [3,4].
n2:mentions: n3:4938153

Subject Item: _:vb8363691
rdf:type: n2:Context
rdf:value: For this reason, tumor angiogenesis has become an important target for cancer therapy [>>3<<,4]. Vascular endothelial growth factor (VEGF), a primary angiogenic growth factor in many tumor types, binds to and activates VEGFR1 and VEGFR2 [5]. VEGFR2 is the dominant angiogenic signaling receptor, while the function of VEGFR1 is
n2:mentions: n3:12516034

Subject Item: _:vb8363692
rdf:type: n2:Context
rdf:value: For this reason, tumor angiogenesis has become an important target for cancer therapy [3,>>4<<]. Vascular endothelial growth factor (VEGF), a primary angiogenic growth factor in many tumor types, binds to and activates VEGFR1 and VEGFR2 [5]. VEGFR2 is the dominant angiogenic signaling receptor, while the function of VEGFR1 is less
n2:mentions: n3:17396134

Subject Item: _:vb8363693
rdf:type: n2:Context
rdf:value: Vascular endothelial growth factor (VEGF), a primary angiogenic growth factor in many tumor types, binds to and activates VEGFR1 and VEGFR2 [>>5<<]. VEGFR2 is the dominant angiogenic signaling receptor, while the function of VEGFR1 is less defined. As the angiogenic VEGF receptor, VEGFR2 has become a central target in developing anti-angiogenic therapies.
n2:mentions: n3:16282508

Subject Item: _:vb8363694
rdf:type: n2:Context
rdf:value: Bevacizumab (Avastin®, Genetech), which binds to VEGF and prevents VEGF from binding to both VEGFR1 and VEGFR2, was the first clinically approved anti-angiogenic therapy [>>6<<]. Bevacizumab was recently approved for the treatment of HER2/NEU-negative breast cancer in combination with chemotherapy, validating the use of anti-angiogenic therapy in this disease [7].
n2:mentions: n3:15175435

Subject Item: _:vb8363695
rdf:type: n2:Context
rdf:value: Bevacizumab was recently approved for the treatment of HER2/NEU-negative breast cancer in combination with chemotherapy, validating the use of anti-angiogenic therapy in this disease [>>7<<]. The clinical success of bevacizumab has amplified the number of anti-VEGF therapies being developed and tested. These therapies may specifically block VEGF, VEGFR1, or VEGFR2, or promiscuously block both VEGFRs as well as other receptor
n2:mentions: n3:18160686

Subject Item: _:vb8363696
rdf:type: n2:Context
rdf:value: These therapies may specifically block VEGF, VEGFR1, or VEGFR2, or promiscuously block both VEGFRs as well as other receptor tyrosine kinases [>>8<<-11].
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Subject Item: _:vb8363697
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rdf:value: We have previously reported the development of a peptoid, GU40C4, that has promising anti-angiogenic activity both in vitro and in vivo [>>12<<]. GU40C4 significantly reduced VEGF-induced VEGFR2 phosphorylation in both PAE-KDR and HUVEC cells.
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rdf:value: Furthermore, GU40C4 significantly reduces VEGF-induced HUVEC proliferation [>>12<<]. GU81, a derivative of GU40C4, was developed to increase binding affinity and therefore in vitro and in vivo efficacy. Peptoids are closely related to peptides, however, peptoids (oligo-N-substituted glycines) are engineered for improved
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rdf:value: Peptoids are closely related to peptides, however, peptoids (oligo-N-substituted glycines) are engineered for improved serum stability and cell permeability compared to peptides [>>13<<]. Peptoids differ from peptides by having the side chain ('R' group) placed on the amide nitrogen of the backbone.
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rdf:value: The MMTV-PyMT model was chosen because tumor progression has been extensively analyzed in this model and closely mirrors the progression of human disease [>>14<<]. Based on our previous work with GU40C4 [12], we hypothesized that GU81 would control breast tumor growth both as a single agent and in combination with chemotherapy. However, our findings indicate that GU81 is not effective as a single
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rdf:value: Based on our previous work with GU40C4 [>>12<<], we hypothesized that GU81 would control breast tumor growth both as a single agent and in combination with chemotherapy.
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