520 results on '"Otto C, Boerman"'
Search Results
2. Combination of sunitinib and 177Lu-labeled antibody cG250 targeted radioimmunotherapy: A promising new therapeutic strategy for patients with advanced renal cell cancer
- Author
-
Jeannette C. Oosterwijk-Wakka, Mirjam C.A. de Weijert, Gerben M. Franssen, Dimitar R. Kolev, Ton A.F.J. de Haan, Otto C. Boerman, Peter F.A. Mulders, and Egbert Oosterwijk
- Subjects
Sunitinib ,RCC ,Combination therapy ,CAIX-targeted radioimmunotherapy ,[177Lu]Lu-cG250 RIT ,Sunitinib resistance ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Sunitinib is an effective treatment for patients with metastatic Renal Cell Carcinoma (mRCC) but ultimately resistance occurs. The aim of this study was to investigate sunitinib resistance in RCCs and to develop therapeutic combination strategies with targeted radioimmunotherapy (RIT).We studied two RCC models, analyzed Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) and AXL/MET expression and performed therapy studies in Balb/cnu/nu mice combining sunitinib and [177Lu]Lu-cG250 RIT (6.5 MBq/10 μg), specifically targeting RCC cells.pAXL and pMET were expressed in sunitinib-resistant SK-RC-52 and absent in sunitinib-sensitive NU12. NGS evaluation showed that expression of VEGFA, VEGFB, VEGFD, PGF and VEGFR1,2,3 was higher and expression of VEGFC and PDGFA was lower in NU12 than in SK-RC-52.Therapy studies combining sunitinib with [177Lu]Lu-cG250 RIT showed that the best response in mice with “resistant” SK-RC-52 tumors was observed with two cycles of Sunitinib and [177Lu]Lu-cG250 RIT, probably due to increased vascular permeability by sunitinib treatment. In the “sensitive” NU12 model, two cycles of [177Lu]Lu-cG250 RIT and two cycles of combination treatment were equally effective.Enhanced therapeutic efficacy was achieved when two agents ([177Lu]Lu-cG250 RIT and sunitinib) that on their own did not induce satisfactory response levels, are combined. Our findings provide a promising new therapeutic strategy for patients with advanced RCC. more...
- Published
- 2022
- Full Text
- View/download PDF
Catalog
3. Imaging carbonic anhydrase IX as a method for monitoring hypoxia-related radioresistance in preclinical head and neck cancer models
- Author
-
Fokko J. Huizing, Bianca A.W. Hoeben, Jasper Lok, Otto C. Boerman, Sandra Heskamp, and Johan Bussink
- Subjects
Head and neck xenografts ,Hypoxia ,CAIX imaging ,Functional imaging ,Girentuximab ,Atovaquone ,Medical physics. Medical radiology. Nuclear medicine ,R895-920 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Background and purpose: Tumor hypoxia is an important cause of radioresistance and is associated with poor outcome.SPECT (Single-photon emission computed tomography) imaging enables visualizing tumor characteristics. We investigated the SPECT-radiotracer [111In]-girentuximab-F(ab’)2 to image Carbonic Anhydrase IX (CAIX), an enzyme upregulated under hypoxic conditions. Materials and methods: Athymic mice with subcutaneous FaDu or SCCNij202 head and neck squamous cell carcinoma (HNSCC) xenografts were treated with atovaquone or were housed in a hypoxic chamber (8% O2). Next, [111In]-girentuximab-F(ab’)2 was injected and 24 h later mice were euthanized for ex vivo biodistribution, autoradiography of the tumor, and immunohistochemical staining of the tumor. Tumor sections were analyzed for hypoxia, CAIX expression, vessels, and perfusion. Also, the effect of atovaquone on microSPECT scans was determined in the FaDu model. Results: Atovaquone decreased CAIX expression by 69% (p = 0.017) compared with control tumors in FaDu, while in the SCCNij202 tumors no difference was observed. Hypoxic breathing did not increase CAIX expression or hypoxia staining in either tumor model, but did affect the necrotic tumor fraction. Ex vivo tracer uptake in the atovaquone treated group did not differ significantly from the control group, despite the difference in CAIX expression. Furthermore, SPECT imaging with [111In]-girentuximab-F(ab’)2 did not discriminate atovaquone-treated versus control tumors. Conclusion: Atovaquone decreased CAIX expression only in the FaDu tumor model. [111In]-girentuximab-F(ab’)2 specifically targets CAIX-expressing areas in HNSCC xenografts, but differences in vessel density and necrosis most likely affected tracer uptake in the tumors and therefore complicated quantification of changes in CAIX expression. more...
- Published
- 2021
- Full Text
- View/download PDF
4. Carcinoembryonic antigen-targeted photodynamic therapy in colorectal cancer models
- Author
-
Fortuné M. K. Elekonawo, Desirée L. Bos, David M. Goldenberg, Otto C. Boerman, and Mark Rijpkema
- Subjects
Colorectal cancer ,Targeted photodynamic therapy ,Carcinoembryonic antigen ,Targeted ,IRDye700DX ,Medical physics. Medical radiology. Nuclear medicine ,R895-920 - Abstract
Abstract Background In colorectal cancer, survival of patients is drastically reduced when complete resection is hampered by involvement of critical structures. Targeted photodynamic therapy (tPDT) is a local and targeted therapy which could play a role in eradicating residual tumor cells after incomplete resection. Since carcinoembryonic antigen (CEA; CEACAM5) is abundantly overexpressed in colorectal cancer, it is a potential target for tPDT of colorectal cancer. Methods To address the potential of CEA-targeted PDT, we compared colorectal cancer cell lines with different CEA-expression levels (SW-48, SW-480, SW-620, SW-1222, WiDr, HT-29, DLD-1, LS174T, and LoVo) under identical experimental conditions. We evaluated the susceptibility to tPDT by varying radiant exposure and concentration of our antibody conjugate (DTPA-hMN-14-IRDye700DX). Finally, we assessed the efficacy of tPDT in vivo in 18 mice (BALB/cAnNRj-Foxn1 nu/nu ) with subcutaneously xenografted LoVo tumors. Results In vitro, the treatment effect of tPDT varied per cell line and was dependent on both radiant exposure and antibody concentration. Under standardized conditions (94.5 J/cm2 and 0.5 μg/μL antibody conjugate concentration), the effect of tPDT was higher in cells with higher CEA availability: SW-1222, LS174T, LoVo, and SW-48 (22.8%, 52.8%, 49.9%, and 51.9% reduction of viable cells, respectively) compared to cells with lower CEA availability. Compared to control groups (light or antibody conjugate only), tumor growth rate was reduced in mice with s.c. LoVo tumors receiving tPDT. Conclusion Our findings suggest cells (and tumors) have different levels of susceptibility for tPDT even though they all express CEA. Furthermore, tPDT can effectively reduce tumor growth in vivo. more...
- Published
- 2019
- Full Text
- View/download PDF
5. A pretargeted multimodal approach for image-guided resection in a xenograft model of colorectal cancer
- Author
-
Fortuné M. K. Elekonawo, Susanne Lütje, Gerben M. Franssen, Desirée L. Bos, David M. Goldenberg, Otto C. Boerman, and Mark Rijpkema
- Subjects
Colorectal cancer ,Pretargeting ,Near-infrared fluorescence ,Image-guided ,Carcinoembryonic antigen ,Medical physics. Medical radiology. Nuclear medicine ,R895-920 - Abstract
Abstract Background Image-guided surgery may improve surgical outcome for colorectal cancer patients. Here, we evaluated the feasibility of a pretargeting strategy for multimodal imaging in colorectal cancer using an anti-carcinoembryonic antigen (CEA) x anti-histamine-succinyl-glycine (HSG) bispecific antibody (TF2) in conjunction with the dual-labeled diHSG peptide (RDC018), using both a fluorophore for near-infrared fluorescence imaging and a chelator for radiolabeling. Methods Nude mice with subcutaneous (s.c) CEA-expressing LS174T human colonic tumors and CEA-negative control tumors were injected with TF2. After 16 h, different doses of 111In-labeled IMP-288 (non-fluorescent) or its fluorescent derivative RDC018 were administered to compare biodistributions. MicroSPECT/CT and near-infrared fluorescence imaging were performed 2 and 24 h after injection. Next, the biodistribution of the dual-labeled humanized anti-CEA IgG antibody [111In]In-DTPA-hMN-14-IRDye800CW (direct targeting) was compared with the biodistribution of 111In-RDC018 in mice with TF2-pretargeted tumors, using fluorescence imaging and gamma counting. Lastly, mice with intraperitoneal LS174T tumors underwent near-infrared fluorescence image-guided resection combined with pre- and post-resection microSPECT/CT imaging. Results 111In-RDC018 showed specific tumor targeting in pretargeted CEA-positive tumors (21.9 ± 4.5 and 10.0 ± 4.7% injected activity per gram (mean ± SD %IA/g), at 2 and 24 hours post-injection (p.i.), respectively) and a biodistribution similar to 111In-IMP288. Both fluorescence and microSPECT/CT images confirmed preferential tumor accumulation. At post mortem dissection, intraperitoneal tumors were successfully identified and removed using pretargeting with TF2 and 111In-RDC018. Conclusion A pretargeted approach for multimodal image-guided resection of colorectal cancer in a preclinical xenograft model is feasible, enables preoperative SPECT/CT, and might facilitate intraoperative fluorescence imaging. more...
- Published
- 2019
- Full Text
- View/download PDF
6. Simlukafusp alfa (FAP-IL2v) immunocytokine is a versatile combination partner for cancer immunotherapy
- Author
-
Inja Waldhauer, Valeria Gonzalez-Nicolini, Anne Freimoser-Grundschober, Tapan K Nayak, Linda Fahrni, Ralf J. Hosse, Danny Gerrits, Edwin J. W. Geven, Johannes Sam, Sabine Lang, Esther Bommer, Virginie Steinhart, Elisabeth Husar, Sara Colombetti, Erwin Van Puijenbroek, Markus Neubauer, J. Mark Cline, Pradeep K. Garg, Gregory Dugan, Federica Cavallo, Gonzalo Acuna, Jehad Charo, Volker Teichgräber, Stefan Evers, Otto C. Boerman, Marina Bacac, Ekkehard Moessner, Pablo Umaña, and Christian Klein more...
- Subjects
FAP-il2v ,rg7461 ,immunocytokine ,interleukin-2 ,fibroblast activation protein ,Therapeutics. Pharmacology ,RM1-950 ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Simlukafusp alfa (FAP-IL2v, RO6874281/RG7461) is an immunocytokine comprising an antibody against fibroblast activation protein α (FAP) and an IL-2 variant with a retained affinity for IL-2Rβγ > IL-2 Rβγ and abolished binding to IL-2 Rα. Here, we investigated the immunostimulatory properties of FAP-IL2v and its combination with programmed cell death protein 1 (PD-1) checkpoint inhibition, CD40 agonism, T cell bispecific and antibody-dependent cellular cytotoxicity (ADCC)-mediating antibodies. The binding and immunostimulatory properties of FAP-IL2v were investigated in vitro and compared with FAP-IL2wt. Tumor targeting was investigated in tumor-bearing mice and in a rhesus monkey. The ability of FAP-IL2v to potentiate the efficacy of different immunotherapies was investigated in different xenograft and syngeneic murine tumor models. FAP-IL2v bound IL-2 Rβγ and FAP with high affinity in vitro, inducing dose-dependent proliferation of natural killer (NK) cells and CD4+/CD8+ T cells while being significantly less potent than FAP-IL2wt in activating immunosuppressive regulatory T cells (Tregs). T cells activated by FAP-IL2v were less sensitive to Fas-mediated apoptosis than those activated by FAP-IL2wt. Imaging studies demonstrated improved tumor targeting of FAP-IL2v compared to FAP-IL2wt. Furthermore, FAP-IL2v significantly enhanced the in vitro and in vivo activity of therapeutic antibodies that mediate antibody-dependent or T cell-dependent cellular cytotoxicity (TDCC) and of programmed death-ligand 1 (PD-L1) checkpoint inhibition. The triple combination of FAP-IL2v with an anti-PD-L1 antibody and an agonistic CD40 antibody was most efficacious. These data indicate that FAP-IL2v is a potent immunocytokine that potentiates the efficacy of different T- and NK-cell-based cancer immunotherapies. more...
- Published
- 2021
- Full Text
- View/download PDF
7. Non-invasive in vivo determination of viable islet graft volume by 111In-exendin-3
- Author
-
Wael A. Eter, Inge Van der Kroon, Karolina Andralojc, Mijke Buitinga, Stefanie M. A. Willekens, Cathelijne Frielink, Desiree Bos, Lieke Joosten, Otto C. Boerman, Maarten Brom, and Martin Gotthardt
- Subjects
Medicine ,Science - Abstract
Abstract Pancreatic islet transplantation is a promising therapy for patients with type 1 diabetes. However, the duration of long-term graft survival is limited due to inflammatory as well as non-inflammatory processes and routine clinical tests are not suitable to monitor islet survival. 111In-exendin-SPECT (single photon emission computed tomography) is a promising method to non-invasively image islets after transplantation and has the potential to help improve the clinical outcome. Whether 111In-exendin-SPECT allows detecting small differences in beta-cell mass (BCM) and measuring the actual volume of islets that were successfully engrafted has yet to be demonstrated. Here, we evaluated the performance of 111In-exendin-SPECT using an intramuscular islet transplantation model in C3H mice. In vivo imaging of animals transplanted with 50, 100, 200, 400 and 800 islets revealed an excellent linear correlation between SPECT quantification of 111In-exendin uptake and insulin-positive area of islet transplants, demonstrating that 111In-exendin-SPECT specifically and accurately measures BCM. The high sensitivity of the method allowed measuring small differences in graft volumes, including grafts that contained less than 50 islets. The presented method is reliable, convenient and holds great potential for non-invasive monitoring of BCM after islet transplantation in humans. more...
- Published
- 2017
- Full Text
- View/download PDF
8. Preclinical evaluation of PAC1 targeting with radiolabeled Maxadilan
- Author
-
Lieke Joosten, Maarten Brom, Martin K. H. Schäfer, Otto C. Boerman, Eberhard Weihe, and Martin Gotthardt
- Subjects
Medicine ,Science - Abstract
Abstract There is an ongoing search for new tracers to optimize imaging of beta cell-derived tumors (insulinomas). The PAC1 receptor, expressed by insulinomas, can be used for targeting of these tumors. Here, we investigated whether radiolabeled maxadilan could be used for insulinoma imaging. Maxadilan was C- or N-terminally conjugated with DTPA (termed maxadilan-DPTA or DTPA-maxadilan respectively). BALB/c nude mice bearing subcutaneous INS-1 tumors were injected with either In-111-labeled maxadilan-DTPA or In-111-DTPA-maxadilan. Biodistribution studies were carried out at 1, 2 and 4 hours after injection and SPECT/CT imaging 1 and 4 hours after injection of maxadilan-DTPA-111In. Radiolabeling of maxadilan-DTPA (680 MBq/nmol) was more efficient than of DTPA-maxadilan (55 MBq/nmol). Conjugation with DTPA slightly reduced receptor binding affinity in vitro: IC50 values were 3.2, 21.0 and 21.0 nM for maxadilan, natIn-DTPA-maxadilan and maxadilan-DTPA-natIn respectively. Upon i.v. injection maxadilan-DTPA-111In accumulated specifically in INS-1 tumors (7.30 ± 1.87%ID/g) and in the pancreas (3.82 ± 0.22%ID/g). INS-1 tumors were clearly visualized by small animal SPECT/CT. In conclusion, this study showed that the high affinity of maxadilan to the PAC1 receptor was maintained after DTPA conjugation. Furthermore, radiolabeled maxadilan-DTPA accumulated specifically in INS-1 tumors and, therefore, may qualify as a useful tracer to image insulinomas. more...
- Published
- 2017
- Full Text
- View/download PDF
9. Data from PD-L1 microSPECT/CT Imaging for Longitudinal Monitoring of PD-L1 Expression in Syngeneic and Humanized Mouse Models for Cancer
- Author
-
Willemijn A. Hobo, Erik H.J.G. Aarntzen, Harry Dolstra, Otto C. Boerman, Johan Bussink, Daniel Olive, Jeannette Cany, Soley Thordardottir, Gerwin W. Sandker, Janneke D.M. Molkenboer-Kuenen, Peter J. Wierstra, and Sandra Heskamp more...
- Abstract
Antibodies that block the interaction between programmed death ligand 1 (PD-L1) and PD-1 have shown impressive responses in subgroups of patients with cancer. PD-L1 expression in tumors seems to be a prerequisite for treatment response. However, PD-L1 is heterogeneously expressed within tumor lesions and may change upon disease progression and treatment. Imaging of PD-L1 could aid in patient selection. Previously, we showed the feasibility to image PD-L1+ tumors in immunodeficient mice. However, PD-L1 is also expressed on immune cell subsets. Therefore, the aim of this study was to assess the potential of PD-L1 micro single-photon emission tomography/computed tomography (microSPECT/CT) using radiolabeled PD-L1 antibodies to (i) measure PD-L1 expression in two immunocompetent tumor models (syngeneic mice and humanized mice harboring PD-L1 expressing immune cells) and (ii) monitor therapy-induced changes in tumor PD-L1 expression. We showed that radiolabeled PD-L1 antibodies accumulated preferentially in PD-L1+ tumors, despite considerable uptake in certain normal lymphoid tissues (spleen and lymph nodes) and nonlymphoid tissues (duodenum and brown fat). PD-L1 microSPECT/CT imaging could also distinguish between high and low PD-L1–expressing tumors. The presence of PD-L1+ immune cells did not compromise tumor uptake of the human PD-L1 antibodies in humanized mice, and we demonstrated that radiotherapy-induced upregulation of PD-L1 expression in murine tumors could be monitored with microSPECT/CT imaging. Together, these data demonstrate that PD-L1 microSPECT/CT is a sensitive technique to detect variations in tumor PD-L1 expression, and in the future, this technique may enable patient selection for PD-1/PD-L1–targeted therapy. more...
- Published
- 2023
- Full Text
- View/download PDF
10. Supplemental Figure 3 from PD-L1 microSPECT/CT Imaging for Longitudinal Monitoring of PD-L1 Expression in Syngeneic and Humanized Mouse Models for Cancer
- Author
-
Willemijn A. Hobo, Erik H.J.G. Aarntzen, Harry Dolstra, Otto C. Boerman, Johan Bussink, Daniel Olive, Jeannette Cany, Soley Thordardottir, Gerwin W. Sandker, Janneke D.M. Molkenboer-Kuenen, Peter J. Wierstra, and Sandra Heskamp more...
- Abstract
Supplemental Figure 3
- Published
- 2023
- Full Text
- View/download PDF
11. Supplemental Figure 1 from PD-L1 microSPECT/CT Imaging for Longitudinal Monitoring of PD-L1 Expression in Syngeneic and Humanized Mouse Models for Cancer
- Author
-
Willemijn A. Hobo, Erik H.J.G. Aarntzen, Harry Dolstra, Otto C. Boerman, Johan Bussink, Daniel Olive, Jeannette Cany, Soley Thordardottir, Gerwin W. Sandker, Janneke D.M. Molkenboer-Kuenen, Peter J. Wierstra, and Sandra Heskamp more...
- Abstract
Supplemental Figure 1
- Published
- 2023
- Full Text
- View/download PDF
12. Supplemental Figure 2 from PD-L1 microSPECT/CT Imaging for Longitudinal Monitoring of PD-L1 Expression in Syngeneic and Humanized Mouse Models for Cancer
- Author
-
Willemijn A. Hobo, Erik H.J.G. Aarntzen, Harry Dolstra, Otto C. Boerman, Johan Bussink, Daniel Olive, Jeannette Cany, Soley Thordardottir, Gerwin W. Sandker, Janneke D.M. Molkenboer-Kuenen, Peter J. Wierstra, and Sandra Heskamp more...
- Abstract
Supplemental Figure 2
- Published
- 2023
- Full Text
- View/download PDF
13. Supplemental Table 2 from PD-L1 microSPECT/CT Imaging for Longitudinal Monitoring of PD-L1 Expression in Syngeneic and Humanized Mouse Models for Cancer
- Author
-
Willemijn A. Hobo, Erik H.J.G. Aarntzen, Harry Dolstra, Otto C. Boerman, Johan Bussink, Daniel Olive, Jeannette Cany, Soley Thordardottir, Gerwin W. Sandker, Janneke D.M. Molkenboer-Kuenen, Peter J. Wierstra, and Sandra Heskamp more...
- Abstract
Supplemental Table 2
- Published
- 2023
- Full Text
- View/download PDF
14. Supplemental Table 1 from PD-L1 microSPECT/CT Imaging for Longitudinal Monitoring of PD-L1 Expression in Syngeneic and Humanized Mouse Models for Cancer
- Author
-
Willemijn A. Hobo, Erik H.J.G. Aarntzen, Harry Dolstra, Otto C. Boerman, Johan Bussink, Daniel Olive, Jeannette Cany, Soley Thordardottir, Gerwin W. Sandker, Janneke D.M. Molkenboer-Kuenen, Peter J. Wierstra, and Sandra Heskamp more...
- Abstract
Supplemental Table 1
- Published
- 2023
- Full Text
- View/download PDF
15. Supplementary Tables S1-S4 and Supplementary Figures S1-S12 from Digitalis-like Compounds Facilitate Non-Medullary Thyroid Cancer Redifferentiation through Intracellular Ca2+, FOS, and Autophagy-Dependent Pathways
- Author
-
Theo S. Plantinga, Romana T. Netea-Maier, Johannes W.A. Smit, Mihai G. Netea, Hendrik G. Stunnenberg, Jan B. Koenderink, Otto C. Boerman, Danny Gerrits, Herman G. Swarts, Thomas Crezee, and Marika H. Tesselaar more...
- Abstract
Table S1. Overview of selected autophagy activating compounds, their structure, chemical and pharmacological classification and the supplier; Table S2. Significantly upregulated genes in all cell lines at all time points (fold change log2 {greater than or equal to} 1); Table S3. Significantly downregulated genes in all cell lines at all time points (fold change log2 {less than or equal to} -1); Table S4. Physicochemical properties of digitalis-like compounds predicted by ChemBioOf�ce software; Figure S1: Visualization of whole transcriptome data of BC-PAP treated with 50 µM proscillaridin A for 24, 48 or 72 hours, comprising principal component analysis and Venn diagrams of overlapping genes, either up- or downregulated, between 24, 48 and 72 hours time points; Figure S2: Visualization of whole transcriptome data of FTC133 treated with 50 µM digoxin for 24, 48 or 72 hours, comprising principal component analysis and Venn diagrams of overlapping genes, either up- or downregulated, between 24, 48 and 72 hours time points; Figure S3: Visualization of whole transcriptome data of FTC133 treated with 50 µM digoxigenin for 24, 48 or 72 hours, comprising principal component analysis and Venn diagrams of overlapping genes, either up- or downregulated, between 24, 48 and 72 hours time points; Figure S4: Visualization of whole transcriptome data of FTC133 treated with 50 µM proscillaridin A for 24, 48 or 72 hours, comprising principal component analysis and Venn diagrams of overlapping genes, either up- or downregulated, between 24, 48 and 72 hours time points; Figure S5: Visualization of whole transcriptome data of FTC133 treated with 50 µM strophantin K for 24, 48 or 72 hours, comprising principal component analysis and Venn diagrams of overlapping genes, either up- or downregulated, between 24, 48 and 72 hours time points; Figure S6: Visualization of whole transcriptome data of TPC-1 treated with lanatoside C for 24, 48 or 72 hours, comprising principal component analysis and Venn diagrams of overlapping genes, either up- or downregulated, between 24, 48 and 72 hours time points; Figure S7: STRING protein interaction networks of significantly up- or downregulated genes by digitalis-like compounds in all three cell lines and at all three time points; Figure S8: Bonferroni corrected P-value enrichment scores of significantly upregulated pathways by digitalis-like compounds combined for all three cell lines and for all three time points. P-values are generated by using the Gene Ontology (GO) platform category Biological Processes; Figure S9: Expression of JUN after treatment for 48 and 72 hours of BC-PAP, FTC133 and TPC-1 with the indicated digitalis-like compounds. Data are obtained from three independent experiments. Data are means {plus minus} SD. Square boxes represent statistical output of Spearman's rho tests for degree of correlation between expression of JUN with hNIS expression at 48 and 72 hours time points; Figure S10: Gene expression of thyroid transcription factors TTF1, TTF2 and PAX8 in BC-PAP, FTC133 or TPC-1 after treatment with the indicated digitalis-like compounds for 48 or 72 hours. Data are obtained from three independent experiments. Data are means {plus minus} SD; Figure S11: Heatmaps depicting gene expression of ABC transporters and organic anion transporters in untreated and digitalis-like compound treated BC-PAP, FTC133 and TPC-1 (N=6); Figure S12: Full unedited Western blot pictures, cropped pictures are depicted in Figure 1B. more...
- Published
- 2023
- Full Text
- View/download PDF
16. Figure S1 from Targeted Dual-Modality Imaging in Renal Cell Carcinoma: An Ex Vivo Kidney Perfusion Study
- Author
-
Mark Rijpkema, Peter F.A. Mulders, Hans F. Langenhuijsen, Egbert Oosterwijk, Desirée L. Bos, Mirjam de Weijert, Otto C. Boerman, and Marlène C.H. Hekman
- Abstract
Schematic overview of the different steps of the perfusion experiment.
- Published
- 2023
- Full Text
- View/download PDF
17. Supplementary Figure 1 from Route of Administration Modulates the Induction of Dendritic Cell Vaccine–Induced Antigen-Specific T Cells in Advanced Melanoma Patients
- Author
-
Carl G. Figdor, Cornelis J.A. Punt, Gosse J. Adema, Sophie Lucas, Otto C. Boerman, Wim J.G. Oyen, Roel Mus, Michelle M. van Rossum, Sandra Croockewit, Annemiek J. de Boer, Mandy W.M.M. van de Rakt, Nicole M. Scharenborg, Joannes F.M. Jacobs, Erik H.J.G. Aarntzen, Annechien J.A. Lambeck, Gerty Schreibelt, I. Jolanda M. de Vries, and W. Joost Lesterhuis more...
- Abstract
PDF file - 41K, Clinical protocol and immunization schedule.
- Published
- 2023
- Full Text
- View/download PDF
18. Video S1 from Targeted Dual-Modality Imaging in Renal Cell Carcinoma: An Ex Vivo Kidney Perfusion Study
- Author
-
Mark Rijpkema, Peter F.A. Mulders, Hans F. Langenhuijsen, Egbert Oosterwijk, Desirée L. Bos, Mirjam de Weijert, Otto C. Boerman, and Marlène C.H. Hekman
- Abstract
Video made with the laparoscopic fluorescence camera during experiment #1.
- Published
- 2023
- Full Text
- View/download PDF
19. Supplementary Materials- figure legends from Targeted Dual-Modality Imaging in Renal Cell Carcinoma: An Ex Vivo Kidney Perfusion Study
- Author
-
Mark Rijpkema, Peter F.A. Mulders, Hans F. Langenhuijsen, Egbert Oosterwijk, Desirée L. Bos, Mirjam de Weijert, Otto C. Boerman, and Marlène C.H. Hekman
- Abstract
Supplementary Materials- figure legends
- Published
- 2023
- Full Text
- View/download PDF
20. Data from Targeted Dual-Modality Imaging in Renal Cell Carcinoma: An Ex Vivo Kidney Perfusion Study
- Author
-
Mark Rijpkema, Peter F.A. Mulders, Hans F. Langenhuijsen, Egbert Oosterwijk, Desirée L. Bos, Mirjam de Weijert, Otto C. Boerman, and Marlène C.H. Hekman
- Abstract
Purpose: Antibodies labeled with both a near-infrared fluorescent dye and a radionuclide can be used for tumor-targeted intraoperative dual-modality imaging. Girentuximab is a chimeric monoclonal antibody against carbonic anhydrase IX (CAIX), an antigen expressed in 95% of clear cell renal cell carcinoma (ccRCC). This study aimed to assess the feasibility of targeted dual-modality imaging with 111In-girentuximab-IRDye800CW using ex vivo perfusion of human tumorous kidneys.Experimental Design: Seven radical nephrectomy specimens from patients with ccRCC were perfused during 11 to 15 hours with dual-labeled girentuximab and subsequently rinsed during 2.5 to 4 hours with Ringer's Lactate solution. Then, dual-modality imaging was performed on a 5- to 10-mm-thick lamella of the kidney. Fluorescence imaging was performed with a clinical fluorescence camera set-up as applied during image-guided surgery. The distribution of Indium-111 in the slice of tumor tissue was visualized by autoradiography. In two perfusions, an additional dual-labeled control antibody was added to demonstrate specific accumulation of dual-labeled girentuximab in CAIX-expressing tumor tissue.Results: Both radionuclide and fluorescence imaging clearly visualized uptake in tumor tissue and tumor-to-normal tissue borders, as confirmed (immuno)histochemically and by gamma counting. Maximum uptake of girentuximab in tumor tissue was 0.33% of the injected dose per gram (mean, 0.12 %ID/g; range, 0.01–0.33 %ID/g), whereas maximum uptake in the normal kidney tissue was 0.04 %ID/g (mean, 0.02 %ID/g; range, 0.00–0.04 %ID/g).Conclusions: Dual-labeled girentuximab accumulated specifically in ccRCC tissue, indicating the feasibility of dual-modality imaging to detect ccRCC. A clinical study to evaluate intraoperative dual-modality imaging in patients with ccRCC has been initiated. Clin Cancer Res; 22(18); 4634–42. ©2016 AACR. more...
- Published
- 2023
- Full Text
- View/download PDF
21. Data from Predicting IGF-1R Therapy Response in Bone Sarcomas: Immuno-SPECT Imaging with Radiolabeled R1507
- Author
-
Winette T.A. van der Graaf, Otto C. Boerman, Wim J.G. Oyen, Peter J. Houghton, Hanneke W.M. van Laarhoven, Melissa H.S. Roeffen, Sandra Heskamp, Janneke D.M. Molkenboer-Kuenen, Addy C.M. van de Luijtgaarden, Yvonne M.H. Versleijen-Jonkers, and Emmy D.G. Fleuren more...
- Abstract
Purpose: To investigate whether indium-111–labeled R1507 (111In-R1507) immuno-SPECT (single—photon emission computed tomography), a novel noninvasive, in vivo screening method to visualize membranous insulin-like growth factor 1 receptor (IGF-1R) expression and accessibility, can be used to predict IGF-1R treatment (R1507) response in bone sarcomas.Experimental Design: BALB/c nude mice were subcutaneously implanted with IGF-1R–expressing human bone sarcoma xenografts (OS-1, EW-5, and EW-8) which showed high, modest, or no response, respectively, to R1507, a monoclonal antibody targeting the extracellular domain of IGF-1R. An IGF-1R–negative tumor (OS-33), unresponsive to IGF-1R inhibitors, was examined as well. Mice were injected with 111In-R1507. Biodistribution and immuno-SPECT/computed tomography imaging studies were carried out 1, 3, and 7 days p.i. in mice with OS-1 and EW-5 xenografts and 3 days p.i. in mice with EW-8 and OS-33 xenografts.Results: Biodistribution studies showed specific accumulation of 111In-R1507 in OS-1 and EW-5 xenografts (27.5 ± 6.5%ID/g and 14.0 ± 2.8%ID/g, 3 days p.i., respectively). Most importantly, 111In-R1507 uptake in IGF-1R positive, but unresponsive, EW-8 xenografts (6.5 ± 1.5%ID/g, 3 days p.i.) was similar to that of the IGF-1R–negative OS-33 tumor (5.5 ± 0.6%ID/g, 3 days p.i.). Uptake in normal tissues was low and nonspecific. Corresponding immuno-SPECT images clearly discriminated between high, modest, and nonresponding tumors by showing a homogeneous (OS-1), heterogeneous (EW-5), or nonspecific (EW-8 and OS-33) tumor uptake of 111In-R1507.Conclusions:111In-R1507 immuno-SPECT is an excellent method to visualize membranous IGF-1R expression and target accessibility in vivo in human bone sarcoma xenografts and may serve as an independent marker to predict IGF-1R therapy (R1507) response in bone sarcoma patients. Clin Cancer Res; 17(24); 7693–703. ©2011 AACR. more...
- Published
- 2023
- Full Text
- View/download PDF
22. Supplementary Figure 2 from Route of Administration Modulates the Induction of Dendritic Cell Vaccine–Induced Antigen-Specific T Cells in Advanced Melanoma Patients
- Author
-
Carl G. Figdor, Cornelis J.A. Punt, Gosse J. Adema, Sophie Lucas, Otto C. Boerman, Wim J.G. Oyen, Roel Mus, Michelle M. van Rossum, Sandra Croockewit, Annemiek J. de Boer, Mandy W.M.M. van de Rakt, Nicole M. Scharenborg, Joannes F.M. Jacobs, Erik H.J.G. Aarntzen, Annechien J.A. Lambeck, Gerty Schreibelt, I. Jolanda M. de Vries, and W. Joost Lesterhuis more...
- Abstract
PDF file - 55K, Consort flow chart.
- Published
- 2023
- Full Text
- View/download PDF
23. Data from Route of Administration Modulates the Induction of Dendritic Cell Vaccine–Induced Antigen-Specific T Cells in Advanced Melanoma Patients
- Author
-
Carl G. Figdor, Cornelis J.A. Punt, Gosse J. Adema, Sophie Lucas, Otto C. Boerman, Wim J.G. Oyen, Roel Mus, Michelle M. van Rossum, Sandra Croockewit, Annemiek J. de Boer, Mandy W.M.M. van de Rakt, Nicole M. Scharenborg, Joannes F.M. Jacobs, Erik H.J.G. Aarntzen, Annechien J.A. Lambeck, Gerty Schreibelt, I. Jolanda M. de Vries, and W. Joost Lesterhuis more...
- Abstract
Purpose: It is unknown whether the route of administration influences dendritic cell (DC)-based immunotherapy. We compared the effect of intradermal versus intranodal administration of a DC vaccine on induction of immunologic responses in melanoma patients and examined whether concomitant administration of interleukin (IL)-2 increases the efficacy of the DC vaccine.Experimental Design: HLA-A2.1+ melanoma patients scheduled for regional lymph node dissection were vaccinated four times biweekly via intradermal or intranodal injection with 12 × 106 to 17 × 106 mature DCs loaded with tyrosinase and gp100 peptides together with keyhole limpet hemocyanin (KLH). Half of the patients also received low-dose IL-2 (9 MIU daily for 7 days starting 3 days after each vaccination). KLH-specific B- and T-cell responses were monitored in blood. gp100- and tyrosinase-specific T-cell responses were monitored in blood by tetramer analysis and in biopsies from delayed-type hypersensitivity (DTH) skin tests by tetramer and functional analyses with 51Cr release assays or IFNγ release, following coculture with peptide-pulsed T2 cells or gp100- or tyrosinase-expressing tumor cells.Results: In 19 of 43 vaccinated patients, functional tumor antigen–specific T cells could be detected. Although significantly more DCs migrated to adjacent lymph nodes upon intranodal vaccination, this was also highly variable with a complete absence of migration in 7 of 24 intranodally vaccinated patients. Intradermal vaccinations proved superior in inducing functional tumor antigen–specific T cells. Coadministration of IL-2 did not further augment the antigen-specific T-cell response but did result in higher regulatory T-cell frequencies.Conclusion: Intradermal vaccination resulted in superior antitumor T-cell induction when compared with intranodal vaccination. No advantage of additional IL-2 treatment could be shown. Clin Cancer Res; 17(17); 5725–35. ©2011 AACR. more...
- Published
- 2023
- Full Text
- View/download PDF
24. Supplementary Methods, Figures 1-3 from Predicting IGF-1R Therapy Response in Bone Sarcomas: Immuno-SPECT Imaging with Radiolabeled R1507
- Author
-
Winette T.A. van der Graaf, Otto C. Boerman, Wim J.G. Oyen, Peter J. Houghton, Hanneke W.M. van Laarhoven, Melissa H.S. Roeffen, Sandra Heskamp, Janneke D.M. Molkenboer-Kuenen, Addy C.M. van de Luijtgaarden, Yvonne M.H. Versleijen-Jonkers, and Emmy D.G. Fleuren more...
- Abstract
PDF file - 2.8MB
- Published
- 2023
- Full Text
- View/download PDF
25. Supplementary Table 2 from Natural Human Plasmacytoid Dendritic Cells Induce Antigen-Specific T-Cell Responses in Melanoma Patients
- Author
-
I. Jolanda M. de Vries, Carl G. Figdor, Cornelis J.A. Punt, Pierre G. Coulie, Gregor Winkels, Michelle van Rossum, Wim J.G. Oyen, Sandra Croockewit, Otto C. Boerman, Daniel Benitez-Ribas, Barbara M. Schulte, Gerty Schreibelt, Tetsuro Baba, Erik H.J.G. Aarntzen, and Jurjen Tel more...
- Abstract
Supplementary Table 2 PDF file - 30K, Patient characteristics and historical controls
- Published
- 2023
- Full Text
- View/download PDF
26. Supplementary Figure 2 from Natural Human Plasmacytoid Dendritic Cells Induce Antigen-Specific T-Cell Responses in Melanoma Patients
- Author
-
I. Jolanda M. de Vries, Carl G. Figdor, Cornelis J.A. Punt, Pierre G. Coulie, Gregor Winkels, Michelle van Rossum, Wim J.G. Oyen, Sandra Croockewit, Otto C. Boerman, Daniel Benitez-Ribas, Barbara M. Schulte, Gerty Schreibelt, Tetsuro Baba, Erik H.J.G. Aarntzen, and Jurjen Tel more...
- Abstract
Supplementary Figure 2 PDF file - 46K, Supplementary Figure 2 Plasmacytoid DCs acquire CCL21-driven chemotactic ability upon activation
- Published
- 2023
- Full Text
- View/download PDF
27. Supplementary Figure 1 from Natural Human Plasmacytoid Dendritic Cells Induce Antigen-Specific T-Cell Responses in Melanoma Patients
- Author
-
I. Jolanda M. de Vries, Carl G. Figdor, Cornelis J.A. Punt, Pierre G. Coulie, Gregor Winkels, Michelle van Rossum, Wim J.G. Oyen, Sandra Croockewit, Otto C. Boerman, Daniel Benitez-Ribas, Barbara M. Schulte, Gerty Schreibelt, Tetsuro Baba, Erik H.J.G. Aarntzen, and Jurjen Tel more...
- Abstract
Supplementary Figure 1 PDF file - 34K, Supplementary Figure 1 CliniMACS-based pDC isolation is feasible
- Published
- 2023
- Full Text
- View/download PDF
28. Supplementary Table 1 from Natural Human Plasmacytoid Dendritic Cells Induce Antigen-Specific T-Cell Responses in Melanoma Patients
- Author
-
I. Jolanda M. de Vries, Carl G. Figdor, Cornelis J.A. Punt, Pierre G. Coulie, Gregor Winkels, Michelle van Rossum, Wim J.G. Oyen, Sandra Croockewit, Otto C. Boerman, Daniel Benitez-Ribas, Barbara M. Schulte, Gerty Schreibelt, Tetsuro Baba, Erik H.J.G. Aarntzen, and Jurjen Tel more...
- Abstract
Supplementary Table 1 PDF file - 29K, Induration (mm) of the different injection sites in the DTH skin test
- Published
- 2023
- Full Text
- View/download PDF
29. Successful Combination of Sunitinib and Girentuximab in Two Renal Cell Carcinoma Animal Models: A Rationale for Combination Treatment of Patients with Advanced RCC
- Author
-
Jeannette C. Oosterwijk-Wakka, Mirjam C.A. de Weijert, Gerben M. Franssen, William P.J. Leenders, Jeroen A.W.M. van der Laak, Otto C. Boerman, Peter F.A. Mulders, and Egbert Oosterwijk
- Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Anti-angiogenic treatment with tyrosine kinase inhibitors (TKI) has lead to an impressive increase in progression-free survival for patients with metastatic RCC (mRCC), but mRCC remains largely incurable. We combined sunitinib, targeting the endothelial cells with Girentuximab (monoclonal antibody cG250, recognizing carbonic anhydrase IX (CAIX) targeting the tumor cells to study the effect of sunitinib on the biodistribution of Girentuximab because combination of modalities targeting tumor vasculature and tumor cells might result in improved effect. Nude mice with human RCC xenografts (NU12, SK-RC-52) were treated orally with 0.8 mg/day sunitinib, or vehicle for 7 to 14 days. Three days before start or cessation of treatment mice were injected i.v. with 0.4 MBq/5 μg 111In-Girentuximab followed by biodistribution studies. Immunohistochemical analyses were performed to study the tumor vasculature and CAIX expression and to confirm Girentuximab uptake. NU12 appeared to represent a sunitinib sensitive tumor: sunitinib treatment resulted in extensive necrosis and decreased microvessel density (MVD). Accumulation of Girentuximab was significantly decreased when sunitinib treatment preceded the antibody injection but remained unchanged when sunitinib followed Girentuximab injection. Cessation of therapy led to a rapid neovascularization, reminiscent of a tumor flare. SK-RC-52 appeared to represent a sunitinib-resistant tumor: (central) tumor necrosis was minimal and MVD was not affected. Sunitinib treatment resulted in increased Girentuximab uptake, regardless of the sequence of treatment. These data indicate that sunitinib can be combined with Girentuximab. Since these two modalities have different modes of action, this combination might lead to enhanced therapeutic efficacy. more...
- Published
- 2015
- Full Text
- View/download PDF
30. Imaging carbonic anhydrase IX as a method for monitoring hypoxia-related radioresistance in preclinical head and neck cancer models
- Author
-
Sandra Heskamp, Jasper Lok, Fokko J. Huizing, Otto C. Boerman, Bianca A.W. Hoeben, and Johan Bussink
- Subjects
R895-920 ,Rare cancers Radboud Institute for Molecular Life Sciences [Radboudumc 9] ,Girentuximab ,Medical physics. Medical radiology. Nuclear medicine ,All institutes and research themes of the Radboud University Medical Center ,Radioresistance ,Spect imaging ,medicine ,Radiology, Nuclear Medicine and imaging ,Original Research Article ,Hypoxia ,RC254-282 ,Atovaquone ,Radiation ,Tumor hypoxia ,business.industry ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,Head and neck squamous-cell carcinoma ,Cancer research ,Immunohistochemistry ,Head and neck xenografts ,CAIX imaging ,Functional imaging ,business ,Ex vivo ,Rare cancers Radboud Institute for Health Sciences [Radboudumc 9] ,medicine.drug - Abstract
Background and purpose Tumor hypoxia is an important cause of radioresistance and is associated with poor outcome. SPECT (Single-photon emission computed tomography) imaging enables visualizing tumor characteristics. We investigated the SPECT-radiotracer [111In]-girentuximab-F(ab’)2 to image Carbonic Anhydrase IX (CAIX), an enzyme upregulated under hypoxic conditions. Materials and methods Athymic mice with subcutaneous FaDu or SCCNij202 head and neck squamous cell carcinoma (HNSCC) xenografts were treated with atovaquone or were housed in a hypoxic chamber (8% O2). Next, [111In]-girentuximab-F(ab’)2 was injected and 24 h later mice were euthanized for ex vivo biodistribution, autoradiography of the tumor, and immunohistochemical staining of the tumor. Tumor sections were analyzed for hypoxia, CAIX expression, vessels, and perfusion. Also, the effect of atovaquone on microSPECT scans was determined in the FaDu model. Results Atovaquone decreased CAIX expression by 69% (p = 0.017) compared with control tumors in FaDu, while in the SCCNij202 tumors no difference was observed. Hypoxic breathing did not increase CAIX expression or hypoxia staining in either tumor model, but did affect the necrotic tumor fraction. Ex vivo tracer uptake in the atovaquone treated group did not differ significantly from the control group, despite the difference in CAIX expression. Furthermore, SPECT imaging with [111In]-girentuximab-F(ab’)2 did not discriminate atovaquone-treated versus control tumors. Conclusion Atovaquone decreased CAIX expression only in the FaDu tumor model. [111In]-girentuximab-F(ab’)2 specifically targets CAIX-expressing areas in HNSCC xenografts, but differences in vessel density and necrosis most likely affected tracer uptake in the tumors and therefore complicated quantification of changes in CAIX expression. more...
- Published
- 2021
- Full Text
- View/download PDF
31. Optimization of Dual-Labeled Antibodies for Targeted Intraoperative Imaging of Tumors
- Author
-
Mark Rijpkema, Desirée L. Bos, Alex S. Cornelissen, Gerben M. Franssen, David M. Goldenberg, Wim J. Oyen, and Otto C. Boerman
- Subjects
Biology (General) ,QH301-705.5 ,Medical technology ,R855-855.5 - Abstract
For intraoperative imaging, antibodies labeled with both a radionuclide and a fluorophore may be used to tag the tumor lesion with a radiolabel and a fluorescent signal at high tumor to background ratios. However, labeling antibodies with fluorescent moieties may affect the in vivo behavior of the antibody depending on the dye to antibody substitution ratio. To investigate the optimal substitution ratio for use in dual-modality image-guided surgery, we conjugated three different antibodies, MN-14 (anti-CEACAM5), girentuximab (anti-CAIX), and cetuximab (anti-EGFR), with both diethylene triamine pentaacetic acid (DTPA, for labeling with 111 In) and IRdye 800CW at dye to antibody ratios of 0, 1, 1.5, 2, and 3 and assessed in vivo behavior. Biodistribution studies showed that at high dye to antibody ratios, liver uptake of the dual-labeled antibodies increased, whereas tumor uptake decreased. Conversely, very low ratios may not be optimal either because in that case, only a few antibody molecules will be dual-labeled (i.e., contain both a DTPA and an IRDye 800CW moiety), which may complicate interpretation of dual-modality data. The present study shows that, provided that the chelator to antibody ratio is high enough, a dye to antibody ratio in the range of 1 to 1.5 is optimal for antibody-targeted dual-modality imaging applications. However, the optimal configuration is antibody dependent and should be determined for each dual-labeled antibody individually. more...
- Published
- 2015
- Full Text
- View/download PDF
32. Upregulation of IGF-1R expression during neoadjuvant therapy predicts poor outcome in breast cancer patients.
- Author
-
Sandra Heskamp, Otto C Boerman, Janneke D M Molkenboer-Kuenen, Carla A Wauters, Luc J A Strobbe, Caroline M P W Mandigers, Peter Bult, Wim J G Oyen, Winette T A van der Graaf, and Hanneke W M van Laarhoven more...
- Subjects
Medicine ,Science - Abstract
The insulin-like growth factor 1 receptor (IGF-1R) may be involved in the development of resistance against conventional cancer treatment. The aim of this study was to assess whether IGF-1R expression of breast tumors changes during neoadjuvant therapy and to study whether these changes were associated with survival.Paraffin embedded tumor tissue was collected from pretreatment biopsies and surgical resections of 62 breast cancer patients who were treated with neoadjuvant chemotherapy or endocrine therapy. IGF-1R expression was determined immunohistochemically and compared before and after treatment.High membranous IGF-1R expression at diagnosis correlated significantly with ER positivity, low tumor stage (stage I/II) and longer overall survival (p < 0.05). After neoadjuvant treatment, membranous IGF-1R expression remained the same in 41 (65%) tumors, was upregulated in 11 (18%) tumors and downregulated in 11 (18%) tumors. Changes in membranous IGF-1R expression were associated with overall survival (log-rank test: p = 0.013, multivariate cox-regression: p = 0.086). Mean overall survival time for upregulation, no change, and downregulation in IGF-1R expression was 3.0 ± 0.5 years, 7.3 ± 1.0 years and 15.0 ± 1.8 years, respectively. Changes in other parameters were not significantly associated with survival.Neoadjuvant therapy can induce changes in IGF-1R expression. Upregulation of IGF-1R expression after neoadjuvant treatment is a poor prognostic factor in breast cancer patients, providing a rationale for incorporating anti-IGF-1R drugs in the management of these patients. more...
- Published
- 2015
- Full Text
- View/download PDF
33. Carcinoembryonic antigen-targeted photodynamic therapy in colorectal cancer models
- Author
-
Mark Rijpkema, Otto C. Boerman, David M. Goldenberg, Desiree Bos, and Fortuné M K Elekonawo
- Subjects
lcsh:Medical physics. Medical radiology. Nuclear medicine ,Colorectal cancer ,medicine.medical_treatment ,lcsh:R895-920 ,Photodynamic therapy ,Targeted therapy ,03 medical and health sciences ,0302 clinical medicine ,Carcinoembryonic antigen ,In vivo ,Medicine ,Radiology, Nuclear Medicine and imaging ,IRDye700DX ,Original Research ,030304 developmental biology ,0303 health sciences ,biology ,business.industry ,Targeted photodynamic therapy ,Targeted ,medicine.disease ,In vitro ,Cell culture ,Urological cancers Radboud Institute for Health Sciences [Radboudumc 15] ,030220 oncology & carcinogenesis ,biology.protein ,Cancer research ,Antibody ,business ,Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19] - Abstract
Background In colorectal cancer, survival of patients is drastically reduced when complete resection is hampered by involvement of critical structures. Targeted photodynamic therapy (tPDT) is a local and targeted therapy which could play a role in eradicating residual tumor cells after incomplete resection. Since carcinoembryonic antigen (CEA; CEACAM5) is abundantly overexpressed in colorectal cancer, it is a potential target for tPDT of colorectal cancer. Methods To address the potential of CEA-targeted PDT, we compared colorectal cancer cell lines with different CEA-expression levels (SW-48, SW-480, SW-620, SW-1222, WiDr, HT-29, DLD-1, LS174T, and LoVo) under identical experimental conditions. We evaluated the susceptibility to tPDT by varying radiant exposure and concentration of our antibody conjugate (DTPA-hMN-14-IRDye700DX). Finally, we assessed the efficacy of tPDT in vivo in 18 mice (BALB/cAnNRj-Foxn1nu/nu) with subcutaneously xenografted LoVo tumors. Results In vitro, the treatment effect of tPDT varied per cell line and was dependent on both radiant exposure and antibody concentration. Under standardized conditions (94.5 J/cm2 and 0.5 μg/μL antibody conjugate concentration), the effect of tPDT was higher in cells with higher CEA availability: SW-1222, LS174T, LoVo, and SW-48 (22.8%, 52.8%, 49.9%, and 51.9% reduction of viable cells, respectively) compared to cells with lower CEA availability. Compared to control groups (light or antibody conjugate only), tumor growth rate was reduced in mice with s.c. LoVo tumors receiving tPDT. Conclusion Our findings suggest cells (and tumors) have different levels of susceptibility for tPDT even though they all express CEA. Furthermore, tPDT can effectively reduce tumor growth in vivo. more...
- Published
- 2019
34. Follow-up imaging after cryoablation of clear cell renal cell carcinoma is feasible using single photon emission computed tomography with 111In-girentuximab
- Author
-
Johan F. Langenhuijsen, Tim J. van Oostenbrugge, Peter F.A. Mulders, Jurgen J. Fütterer, Otto C. Boerman, Sjoerd F. M. Jenniskens, Egbert Oosterwijk, and Wim J.G. Oyen
- Subjects
medicine.medical_treatment ,Early detection ,Rare cancers Radboud Institute for Molecular Life Sciences [Radboudumc 9] ,Single-photon emission computed tomography ,030218 nuclear medicine & medical imaging ,03 medical and health sciences ,0302 clinical medicine ,Renal cell carcinoma ,Urological cancers Radboud Institute for Molecular Life Sciences [Radboudumc 15] ,medicine ,Radiology, Nuclear Medicine and imaging ,Prospective cohort study ,medicine.diagnostic_test ,business.industry ,Girentuximab ,Other Research Radboud Institute for Health Sciences [Radboudumc 0] ,Cryoablation ,General Medicine ,Renal tumor ,medicine.disease ,Clear cell renal cell carcinoma ,Urological cancers Radboud Institute for Health Sciences [Radboudumc 15] ,030220 oncology & carcinogenesis ,Nuclear medicine ,business ,Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19] ,medicine.drug - Abstract
Purpose Detection of residual or recurrent vital renal tumor on follow-up (FU) cross-sectional imaging after ablative therapy is challenging. The specific and high expression levels of carbonic anhydrase IX (CAIX) in clear cell renal cell carcinoma (ccRCC) makes it a suitable target for imaging using radiolabeled anti-CAIX antibody girentuximab. The objective of this study was to evaluate the feasibility of targeted FU imaging 1 month after cryoablation of ccRCC using single photon emission computed tomography (SPECT) after 111In-labeled girentuximab administration. Methods In this prospective study 16 patients underwent 111In-girentuximab-SPECT before MR-guided renal cryoablation between February 2015 and September 2018. In case of tumor targeting 111In-girentuximab-SPECT was repeated 1 month following MR-guided cryoablation. Presence of residual or recurrent vital tumor was assessed on contrast-enhanced cross-sectional imaging during further FU. The standard FU imaging protocol consisted of MRI/CT scans at 1, 3, 6, 12, and 18 months and annually thereafter. Results A total of 10 (63%) patients showed positive tumor targeting on 111In-girentuximab-SPECT before cryoablation and 9 ( 56%) were eligible to undergo FU SPECT. Of the 9 111In-girentuximab-SPECT FU scans, 8 (89%) were considered negative. One (11%) scan showed uptake suggestive for residual vital tumor. Six months after treatment, FU CT showed contrast enhancement suggestive for residual/recurrent disease in the ablated zone at the site of the 111In-girentuximab uptake after treatment. During a mean FU of 21 months (range 1–33) no other cases with residual/recurrent disease were detected. Conclusion FU imaging with 111In-girentuximab-SPECT is feasible after ccRCC cryoablation and may contribute to early detection of residual or recurrent disease. more...
- Published
- 2019
- Full Text
- View/download PDF
35. Quantitative Imaging of the Hypoxia-Related Marker CAIX in Head and Neck Squamous Cell Carcinoma Xenograft Models
- Author
-
Johan Bussink, Sandra Heskamp, Otto C. Boerman, Bianca A.W. Hoeben, Fokko J. Huizing, and Gerben M. Franssen
- Subjects
Pharmaceutical Science ,Mice, Nude ,Endogeny ,02 engineering and technology ,Rare cancers Radboud Institute for Molecular Life Sciences [Radboudumc 9] ,030226 pharmacology & pharmacy ,Article ,03 medical and health sciences ,Mice ,0302 clinical medicine ,All institutes and research themes of the Radboud University Medical Center ,In vivo ,Drug Discovery ,preclinical ,Medicine ,Animals ,girentuximab ,Head and neck cancer ,Carbonic Anhydrase IX ,Tomography, Emission-Computed, Single-Photon ,Tumor hypoxia ,business.industry ,hypoxia ,Squamous Cell Carcinoma of Head and Neck ,Girentuximab ,Antibodies, Monoclonal ,Hypoxia (medical) ,021001 nanoscience & nanotechnology ,medicine.disease ,Head and neck squamous-cell carcinoma ,Immunohistochemistry ,Nitroimidazoles ,Cancer research ,Molecular Medicine ,Autoradiography ,medicine.symptom ,CAIX imaging ,0210 nano-technology ,business ,Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19] ,Ex vivo ,medicine.drug ,Rare cancers Radboud Institute for Health Sciences [Radboudumc 9] - Abstract
Tumor hypoxia plays a major role in radio- and chemotherapy resistance in solid tumors. Carbonic Anhydrase IX (CAIX) is an endogenous hypoxia-related protein, which is associated with poor patient outcome. The quantitative assessment of CAIX expression of tumors may steer cancer treatment by predicting therapy response or patient selection for antihypoxia or CAIX-targeted treatment. Recently, the single-photon emission computerized tomography (SPECT) tracer [111In]In-DTPA-girentuximab-F(ab′)2 was developed and validated for targeting CAIX. The aim of this study was to optimize quantitative microSPECT/CT of CAIX expression in vivo in head and neck tumor models. Athymic mice with subcutaneous SCCNij153 and SCCNij202 head and neck squamous cell carcinoma xenografts were injected with [111In]In-DTPA-girentuximab-F(ab′)2. First, the protein dose, timing, and image acquisition settings were optimized. Tracer uptake was determined by quantitative SPECT, ex vivo radioactivity counting, and by autoradiography of tumor sections. The same tumor sections were immunohistochemically stained for CAIX expression and hypoxia. Highest tumor-normal-tissue contrast was obtained at 24 h after injection of the tracer. A protein dose of 10 μg resulted in the highest tumor-to-muscle ratio at 24 h p.i. Ex vivo biodistribution studies showed a tumor uptake of 3.0 ± 0.6%ID/g and a tumor-to-muscle ratio of 8.7 ± 1.4 (SCCNij153). Quantitative analysis of the SPECT images enabled us to distinguish CAIX antigen blocked from nonblocked tumors, fractions positive for CAIX expression: 0.22 ± 0.02 versus 0.08 ± 0.01 (p < 0.01). Immunohistochemical, autoradiographic, and microSPECT/CT analyses showed a distinct intratumoral spatial correlation between localization of the radiotracer and CAIX expression. Here, we demonstrate that [111In]In-DTPA-girentuximab-F(ab′)2 specifically targets CAIX-expressing cells in head and neck cancer xenografts. SPECT imaging with indium-labeled girentuximab-F(ab′)2 allows quantitative assessment of the fraction of CAIX positive tissue in head and neck cancer xenografts. These results indicate that [111In]In-DTPA-girentuximab-F(ab′)2 is a promising tracer to image hypoxia-related CAIX expression. more...
- Published
- 2019
- Full Text
- View/download PDF
36. Pretargeted imaging and radioimmunotherapy of cancer using antibodies and bioorthogonal chemistry
- Author
-
Otto C. Boerman
- Subjects
Radioimmunodetection ,Radioimmunotherapy ,pretargeting ,tumor-associated antigen ,bispecific antibodies ,Medicine (General) ,R5-920 - Abstract
Selective delivery of radionuclides to tumors may be accomplished using a two-step approach, in which in the first step the tumor is pretargeted with an unlabeled antibody construct and in the second step the tumor is targeted with a radiolabeled small molecule. This results in a more rapid clearance of the radioactivity from normal tissues due to the fast pharmacokinetics of the small molecule as compared to antibodies. In the last decade, several pretargeting approaches have been tested which have shown improved tumor-to-background ratios and thus improved imaging and therapy as compared to directly labeled antibodies. In this review we will discuss the strategies and applications in (pre-)clinical studies of pretargeting concepts based on the use of bispecific antibodies, which are capable of binding to both a target antigen and a radiolabeled peptide. So far, three generations of the bispecific antibody-based pretargeting approach have been studied. The first clinical studies have shown the feasibility and potential for these pretargeting systems to detect and treat tumor lesions. However, to fully integrate the pretargeting approach in clinic, further research should focus on the best regime and pretargeting protocol. Additionally, recent developments in the use of bioorthogonal chemistry for pretargeting of tumors suggest that this chemical pretargeting approach is an attractive alternative strategy for the detection and treatment of tumor lesions. more...
- Published
- 2014
- Full Text
- View/download PDF
37. Optimizing Lutetium 177–Anti–Carbonic Anhydrase IX Radioimmunotherapy in an Intraperitoneal Clear Cell Renal Cell Carcinoma Xenograft Model
- Author
-
Constantijn H.J. Muselaers, Egbert Oosterwijk, Desirée L. Bos, Wim J.G. Oyen, Peter F.A. Mulders, and Otto C. Boerman
- Subjects
Biology (General) ,QH301-705.5 ,Medical technology ,R855-855.5 - Abstract
A new approach in the treatment of clear cell renal carcinoma (ccRCC) is radioimmunotherapy (RIT) using anti-carbonic anhydrase IX (CAIX) antibody G250. To investigate the potential of RIT with lutetium 177 ( 177 Lu)-labeled G250, we conducted a protein dose escalation study and subsequently an RIT study in mice with intraperitoneally growing ccRCC lesions. Mice with intraperitoneal xenografts were injected with 1, 3, 10, 30, or 100 μg of G250 labeled with 10 MBq indium 111 ( 111 In) to determine the optimal protein dose. The optimal protein dose determined with imaging and biodistribution studies was used in a subsequent RIT experiment in three groups of 10 mice with intraperitoneal SK-RC-52 tumors. One group received 13 MBq 177 LU-DOTA-G250, a control group received 13 MBq nonspecific 177 LU-MOPC21, and the second control group was not treated and received 20 MBq 111 In-DOTA-G250. The optimal G250 protein dose to target ccRCC in this model was 10 μg G250. Treatment with 13 MBq 177 LU-DOTA-G250 was well tolerated and resulted in significantly prolonged median survival (139 days) compared to controls (49-53 days, p = .015), indicating that RIT has potential in this metastatic ccRCC model. more...
- Published
- 2014
- Full Text
- View/download PDF
38. Simlukafusp alfa (FAP-IL2v) immunocytokine is a versatile combination partner for cancer immunotherapy
- Author
-
Ralf Hosse, Federica Cavallo, Esther Bommer, Danny Gerrits, Valeria Gonzalez-Nicolini, Marina Bacac, Volker Teichgräber, Stefan Evers, Gregory O. Dugan, Tapan K. Nayak, Erwin van Puijenbroek, Inja Waldhauer, Elisabeth Husar, J. Mark Cline, Virginie Steinhart, Gonzalo Acuna, Ekkehard Moessner, Markus Neubauer, Johannes Sam, Edwin J. W. Geven, Pradeep Garg, Sabine Lang, Jehad Charo, Sara Colombetti, Christian Klein, Linda Fahrni, Anne Freimoser-Grundschober, Otto C. Boerman, and Pablo Umana more...
- Subjects
Interleukin 2 ,fibroblast activation protein ,congenital, hereditary, and neonatal diseases and abnormalities ,immunocytokine ,medicine.medical_treatment ,Recombinant Fusion Proteins ,Immunology ,Antineoplastic Agents ,Lymphocyte Activation ,03 medical and health sciences ,Mice ,All institutes and research themes of the Radboud University Medical Center ,0302 clinical medicine ,Cancer immunotherapy ,Fibroblast activation protein, alpha ,Report ,Endopeptidases ,Immunology and Allergy ,Medicine ,Animals ,Humans ,neoplasms ,030304 developmental biology ,0303 health sciences ,biology ,business.industry ,FAP-il2v ,interleukin-2 ,rg7461 ,Antibodies, Monoclonal ,Membrane Proteins ,Neoplasms, Experimental ,Macaca mulatta ,Xenograft Model Antitumor Assays ,digestive system diseases ,030220 oncology & carcinogenesis ,biology.protein ,Cancer research ,Cytokines ,Immunotherapy ,Antibody ,business ,Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19] ,medicine.drug - Abstract
Simlukafusp alfa (FAP-IL2v, RO6874281/RG7461) is an immunocytokine comprising an antibody against fibroblast activation protein α (FAP) and an IL-2 variant with a retained affinity for IL-2Rβγ > IL-2 Rβγ and abolished binding to IL-2 Rα. Here, we investigated the immunostimulatory properties of FAP-IL2v and its combination with programmed cell death protein 1 (PD-1) checkpoint inhibition, CD40 agonism, T cell bispecific and antibody-dependent cellular cytotoxicity (ADCC)-mediating antibodies. The binding and immunostimulatory properties of FAP-IL2v were investigated in vitro and compared with FAP-IL2wt. Tumor targeting was investigated in tumor-bearing mice and in a rhesus monkey. The ability of FAP-IL2v to potentiate the efficacy of different immunotherapies was investigated in different xenograft and syngeneic murine tumor models. FAP-IL2v bound IL-2 Rβγ and FAP with high affinity in vitro, inducing dose-dependent proliferation of natural killer (NK) cells and CD4+/CD8+ T cells while being significantly less potent than FAP-IL2wt in activating immunosuppressive regulatory T cells (Tregs). T cells activated by FAP-IL2v were less sensitive to Fas-mediated apoptosis than those activated by FAP-IL2wt. Imaging studies demonstrated improved tumor targeting of FAP-IL2v compared to FAP-IL2wt. Furthermore, FAP-IL2v significantly enhanced the in vitro and in vivo activity of therapeutic antibodies that mediate antibody-dependent or T cell-dependent cellular cytotoxicity (TDCC) and of programmed death-ligand 1 (PD-L1) checkpoint inhibition. The triple combination of FAP-IL2v with an anti-PD-L1 antibody and an agonistic CD40 antibody was most efficacious. These data indicate that FAP-IL2v is a potent immunocytokine that potentiates the efficacy of different T- and NK-cell-based cancer immunotherapies. more...
- Published
- 2021
39. 111In-exendin SPECT imaging suggests presence of residual beta cells in patients with longstanding type 1 diabetes
- Author
-
Leo A. B. Joosten, Marcel J.R. Janssen, W. Woliner–van der Weg, B.E. de Galan, Martin Gotthardt, I Kusmartseva, M Atkinson, C.J.J. Tack, Otto C. Boerman, Maarten Brom, Marti Boss, and Martin Béhé
- Subjects
Type 1 diabetes ,business.industry ,Spect imaging ,Medicine ,In patient ,business ,medicine.disease ,Nuclear medicine ,Beta (finance) - Published
- 2021
- Full Text
- View/download PDF
40. Pyruvate‐lactate exchange and glucose uptake in human prostate cancer cell models. A study in xenografts and suspensions by hyperpolarized [1‐13C]pyruvate MRS and [18F]FDG‐PET
- Author
-
Arend Heerschap, Vincent Breukels, Andor Veltien, Sandra Heskamp, Kees C F J Jansen, Otto C. Boerman, Jack A. Schalken, Gerben M. Franssen, Frits H. A. van Heijster, and Tom W. J. Scheenen
- Subjects
Male ,Glucose uptake ,Prostate cancer cell ,18F[FDG] ,Rare cancers Radboud Institute for Molecular Life Sciences [Radboudumc 9] ,13C MRS ,Human prostate ,030218 nuclear medicine & medical imaging ,pyruvate, xenografts ,03 medical and health sciences ,Prostate cancer ,0302 clinical medicine ,Fluorodeoxyglucose F18 ,Cell Line, Tumor ,Urological cancers Radboud Institute for Molecular Life Sciences [Radboudumc 15] ,Pyruvic Acid ,LNCaP ,medicine ,Animals ,Humans ,Tissue Distribution ,Radiology, Nuclear Medicine and imaging ,Pyruvate lactate ,Hyperpolarization (physics) ,Carbon-13 Magnetic Resonance Spectroscopy ,Research Articles ,hyperpolarization ,Spectroscopy ,Mice, Inbred BALB C ,Chemistry ,Prostatic Neoplasms ,medicine.disease ,Xenograft Model Antitumor Assays ,Kinetics ,PET ,Glucose ,Urological cancers Radboud Institute for Health Sciences [Radboudumc 15] ,Positron-Emission Tomography ,Cancer cell ,Lactates ,Cancer research ,prostate cells ,Molecular Medicine ,Energy Metabolism ,Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19] ,030217 neurology & neurosurgery ,Research Article - Abstract
Reprogramming of energy metabolism in the development of prostate cancer can be exploited for a better diagnosis and treatment of the disease. The goal of this study was to determine whether differences in glucose and pyruvate metabolism of human prostate cancer cells with dissimilar aggressivenesses can be detected using hyperpolarized [1‐13C]pyruvate MRS and [18F]FDG‐PET imaging, and to evaluate whether these measures correlate. For this purpose, we compared murine xenografts of human prostate cancer LNCaP cells with those of more aggressive PC3 cells. [1‐13C]pyruvate was hyperpolarized by dissolution dynamic nuclear polarization (dDNP) and [1‐13C]pyruvate to lactate conversion was followed by 13C MRS. Subsequently [18F]FDG uptake was investigated by static and dynamic PET measurements. Standard uptake values (SUVs) for [18F]FDG were significantly higher for xenografts of PC3 compared with those of LNCaP. However, we did not observe a difference in the average apparent rate constant k pl of 13C label exchange from pyruvate to lactate between the tumor variants. A significant negative correlation was found between SUVs from [18F]FDG PET measurements and k pl values for the xenografts of both tumor types. The k pl rate constant may be influenced by various factors, and studies with a range of prostate cancer cells in suspension suggest that LDH inhibition by pyruvate may be one of these. Our results indicate that glucose and pyruvate metabolism in the prostate cancer cell models differs from that in other tumor models and that [18F]FDG‐PET can serve as a valuable complementary tool in dDNP studies of aggressive prostate cancer with [1‐13C]pyruvate., Differences in energy metabolism in murine xenografts of prostate cancer are found using hyperpolarized MR and PET. A significant negative correlation was seen between PET‐derived SUVs and 13C‐MR‐derived k pl values for the xenografts of both tumor types. Standard uptake values (SUV) for [18F]FDG were significantly higher for PC3 compared to LNCaP. Energy metabolism in prostate cancer cell models differ from other tumor models and [18F]FDG‐PET can serve as a complementary tool in dDNP studies of aggressive prostate cancer with [1‐13C]pyruvate. more...
- Published
- 2020
- Full Text
- View/download PDF
41. Early follow-up imaging after cryoablation of clear cell renal cell carcinoma is feasible using single photon emission computed tomography with ¹¹¹In-girentuximab
- Author
-
Wim J.G. Oyen, Otto C. Boerman, T.J. Van Oostenbrugge, Sjoerd F. M. Jenniskens, Egbert Oosterwijk, P.F.A. Mulders, J.J. Fütterer, and Johan F. Langenhuijsen
- Subjects
medicine.diagnostic_test ,business.industry ,Urology ,Girentuximab ,medicine.medical_treatment ,Cryoablation ,Single-photon emission computed tomography ,medicine.disease ,lcsh:Diseases of the genitourinary system. Urology ,lcsh:RC870-923 ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,lcsh:RC254-282 ,Clear cell renal cell carcinoma ,medicine ,Nuclear medicine ,business ,medicine.drug - Published
- 2020
42. Targeting of radioactive platinum-bisphosphonate anticancer drugs to bone of high metabolic activity
- Author
-
Otto C. Boerman, Sandra Heskamp, Uwe Karst, Nicola Margiotta, Michele Iafisco, Michael Brand, Martin Bornhaeuser, Karlijn Codee-van der Schilden, Nandini Asokan, Barbara Crone, Robin A. Nadar, Sander C.G. Leeuwenburgh, Kambiz Farbod, Alessandra Curci, Jeroen J.J.P. van den Beucken, and Lukas Schlatt more...
- Subjects
0301 basic medicine ,Male ,Magnetic Resonance Spectroscopy ,theranostic ,medicine.medical_treatment ,lcsh:Medicine ,Platinum Compounds ,Pharmacology ,Mice ,0302 clinical medicine ,Drug Delivery Systems ,bone-targeting ,Bone cancer ,lcsh:Science ,Zebrafish ,Multidisciplinary ,Molecular medicine ,Diphosphonates ,Chemistry ,Reconstructive and regenerative medicine Radboud Institute for Molecular Life Sciences [Radboudumc 10] ,030220 oncology & carcinogenesis ,Drug delivery ,Toxicity ,Injections, Intravenous ,Systemic administration ,chemistry.chemical_element ,Antineoplastic Agents ,Bone Neoplasms ,Calcium ,Rare cancers Radboud Institute for Molecular Life Sciences [Radboudumc 9] ,Article ,Bone and Bones ,03 medical and health sciences ,Medical research ,In vivo ,medicine ,Bisphosphonate ,Animals ,Radioisotopes ,Tibia ,Bone metastases ,lcsh:R ,In vitro ,Mice, Inbred C57BL ,030104 developmental biology ,lcsh:Q ,195mPlatinum ,Platinum ,Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19] - Abstract
Platinum-based chemotherapeutics exhibit excellent antitumor properties. However, these drugs cause severe side effects including toxicity, drug resistance, and lack of tumor selectivity. Tumor-targeted drug delivery has demonstrated great potential to overcome these drawbacks. Herein, we aimed to design radioactive bisphosphonate-functionalized platinum (195mPt-BP) complexes to confirm preferential accumulation of these Pt-based drugs in metabolically active bone. In vitro NMR studies revealed that release of Pt from Pt BP complexes increased with decreasing pH. Upon systemic administration to mice, Pt-BP exhibited a 4.5-fold higher affinity to bone compared to platinum complexes lacking the bone-seeking bisphosphonate moiety. These Pt-BP complexes formed less Pt-DNA adducts compared to bisphosphonate-free platinum complexes, indicating that in vivo release of Pt from Pt-BP complexes proceeded relatively slow. Subsequently, radioactive 195mPt-BP complexes were synthesized using 195mPt(NO3)2(en) as precursor and injected intravenously into mice. Specific accumulation of 195mPt-BP was observed at skeletal sites with high metabolic activity using micro-SPECT/CT imaging. Furthermore, laser ablation-ICP-MS imaging of proximal tibia sections confirmed that 195mPt BP co-localized with calcium in the trabeculae of mice tibia. more...
- Published
- 2020
- Full Text
- View/download PDF
43. A Clinical Feasibility Study to Image Angiogenesis in Patients with Arteriovenous Malformations Using Ga-68-RGD PET/CT
- Author
-
Janneke D.M. Molkenboer-Kuenen, Ha-Long Nguyen, Miikka Vikkula, Daphne Lobeek, Mark Rijpkema, Laurence M. Boon, Erik H.J.G. Aarntzen, Willemijn M. Klein, Frédérique C.M. Bouwman, Leo J. Schultze Kool, Wim J.G. Oyen, Uta Flucke, Otto C. Boerman, Peter Laverman, and Samantha Y.A. Terry more...
- Subjects
Treatment response ,Angiogenesis ,medicine.medical_treatment ,Vascular damage Radboud Institute for Health Sciences [Radboudumc 16] ,lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4] ,Rare cancers Radboud Institute for Molecular Life Sciences [Radboudumc 9] ,03 medical and health sciences ,0302 clinical medicine ,All institutes and research themes of the Radboud University Medical Center ,medicine ,Radiology, Nuclear Medicine and imaging ,In patient ,Embolization ,PET-CT ,business.industry ,Other Research Radboud Institute for Health Sciences [Radboudumc 0] ,Arteriovenous malformation ,medicine.disease ,Peripheral ,030220 oncology & carcinogenesis ,Urological cancers Radboud Institute for Health Sciences [Radboudumc 15] ,Immunohistochemistry ,Nuclear medicine ,business ,Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19] ,030217 neurology & neurosurgery - Abstract
Arteriovenous malformations (AVMs) have an inherent capacity to form new blood vessels, resulting in excessive lesion growth, and this process is further triggered by the release of angiogenic factors. 68Ga-labeled arginine-glycine-aspartate tripeptide sequence (RGD) PET/CT imaging may provide insight into the angiogenic status and treatment response of AVMs. This clinical feasibility study was performed to demonstrate that 68Ga-RGD PET/CT imaging can be used to quantitatively assess angiogenesis in peripheral AVMs. Methods: Ten patients with a peripheral AVM (mean age, 40 y; 4 men and 6 women) and scheduled for endovascular embolization treatment were prospectively included. All patients underwent 68Ga-RGD PET/CT imaging 60 min after injection (mean dose, 207 ± 5 MBq). Uptake in the AVM, blood pool, and muscle was quantified as SUVmax and SUVpeak, and a descriptive analysis of the PET/CT images was performed. Furthermore, immunohistochemical analysis was performed on surgical biopsy sections of peripheral AVMs to investigate the expression pattern of integrin αvβ3. Results:68Ga-RGD PET/CT imaging showed enhanced uptake in all AVM lesions (mean SUVmax, 3.0 ± 1.1; mean SUVpeak, 2.2 ± 0.9). Lesion-to-blood and lesion-to-muscle ratios were 3.5 ± 2.2 and 4.6 ± 2.8, respectively. Uptake in blood and muscle was significantly higher in AVMs than in background tissue (P = 0.0006 and P = 0.0014, respectively). Initial observations included uptake in multifocal AVM lesions and enhanced uptake in intraosseous components in those AVM cases affecting bone integrity. Immunohistochemical analysis revealed cytoplasmatic and membranous integrin αvβ3 expression in the endothelial cells of AVMs. Conclusion: This feasibility study showed increased uptake in AVMs with angiogenic activity, compared with surrounding tissue without angiogenic activity, suggesting that 68Ga-RGD PET/CT imaging can be used as a tool to quantitatively determine angiogenesis in AVMs. Further studies will be conducted to explore the potential of 68Ga-RGD PET/CT imaging for guiding current treatment decisions and for assessing response to antiangiogenic treatment. more...
- Published
- 2020
44. In Vitro and In Vivo Characterization of Three Ga- and In-Labeled Peptides for Cholecystokinin Receptor Imaging
- Author
-
Susan Roosenburg, Peter Laverman, Lieke Joosten, Annemarie Eek, Floris P.J.T. Rutjes, Floris L. van Delft, and Otto C. Boerman
- Subjects
Biology (General) ,QH301-705.5 ,Medical technology ,R855-855.5 - Abstract
Cholecystokinin (CCK) receptors are overexpressed in several human tumor types, such as medullary thyroid carcinomas and small cell lung cancers. Several ligands for the CCK2 receptor (CCK2R) have been developed for radionuclide targeting of these tumors. In this study, we evaluated whether radiolabeled DOTA-sCCK8 and its stabilized derivative, DOTA-sCCK8[Phe 2 (p-CH 2 SO 3 H), Nle 3,6 ], are suitable for imaging of CCK2R-positive tumors, using DOTA-MG0 as a reference. In vivo targeting of CCK2R-positive tumors with DOTA-sCCK8, DOTA-sCCK8[Phe 2 ( p -CH 2 SO 3 H), Nle 3,6 ], and DOTA-MG0, labeled with 111 In or 68 Ga, was evaluated in BALB/c nude mice with a subcutaneous A431-CCK2R tumor. Biodistribution studies and single-photon emission computed tomography (SPECT) and positron emission tomography (PET) were performed at 1 hour postinjection. All peptides specifically accreted in the CCK2R-expressing tumors. Both 111 In-DOTA-sCCK8 and 111 In-DOTA-sCCK8[Phe 2 ( p -CH 2 SO 3 H), Nle 3,6 ] showed good tumor retention (4.65% ID/g and 5.44% ID/g, respectively, at 4 hours postinjection). On PET/computed tomographic (CT) and SPECT/CT scans, subcutaneous A431-CCK2R tumors were clearly visualized with low uptake of sCCK8 peptides in the intestines. Whereas radiolabeled DOTA-MG0 showed high kidney uptake (70% ID/g), the sCCK8 peptides showed low uptake in the kidneys. Sulfated CCK8 analogues combined high tumor uptake with low retention in the kidney and are therefore promising tracers for imaging of CCK2R-positive tumors. more...
- Published
- 2012
- Full Text
- View/download PDF
45. F-2-Deoxy-2-Fluoro-D-Glucose Positron Emission Tomography, Computed Tomography, and Magnetic Resonance Imaging for the Detection of Experimental Colorectal Liver Metastases
- Author
-
Gabie M. de Jong, Thijs Hendriks, Robert P. Bleichrodt, Helena M. Dekker, Roel D.M. Mus, Martin Gotthardt, Eric P. Visser, Wim J.G. Oyen, and Otto C. Boerman
- Subjects
Biology (General) ,QH301-705.5 ,Medical technology ,R855-855.5 - Abstract
During the treatment of colorectal liver metastases, evaluation of treatment efficacy is of the utmost importance for decision making. The aim of the present study was to explore the ability of preclinical imaging modalities to detect experimental liver metastases. Nine male Wag/Rij rats underwent a laparotomy with intraportal injection of CC531 tumor cells. On days 7, 10, and 14 after tumor induction, sequential positron emission tomography (PET), computed tomography (CT), and magnetic resonance imaging (MRI) scans were acquired of each rat. At each time point, three rats were euthanized and the metastases in the liver were documented histologically. Topographically, the liver was divided into eight segments and the image findings were compared on a segment-by-segment basis with the histopathologic findings. Sixty-four liver segments were analyzed, 20 of which contained tumor deposits. The overall sensitivity of PET, CT, and MRI was 30%, 25%, and 20%, respectively. For the detection of tumors with a histologic diameter exceeding 1 mm ( n = 8), the sensitivity of PET, CT, and MRI was 63%, 38%, and 38%, respectively. The overall specificity of PET, CT, and MRI was 98%, 100%, and 93%, respectively. This study showed encouraging detectability and sensitivity for preclinical imaging of small liver tumors and provides valuable information on the imaging techniques for designing future protocols. more...
- Published
- 2012
- Full Text
- View/download PDF
46. The kinetics and mechanism of bone morphogenetic protein 2 release from calcium phosphate-based implant-coatings
- Author
-
Otto C. Boerman, Ernst B. Hunziker, John A. Jansen, Gang Wu, Corinne Schouten, and Yuelian Liu
- Subjects
Materials science ,Carrier system ,Depot ,Kinetics ,Metals and Alloys ,Biomedical Engineering ,chemistry.chemical_element ,030206 dentistry ,02 engineering and technology ,Calcium ,021001 nanoscience & nanotechnology ,Bone morphogenetic protein 2 ,In vitro ,Biomaterials ,03 medical and health sciences ,0302 clinical medicine ,chemistry ,In vivo ,Ceramics and Composites ,Biophysics ,Implant ,0210 nano-technology - Abstract
Biomimetically deposited calcium phosphate-based coatings of prostheses can serve as a vehicle for the targeted delivery of growth factors to the local implant environment. Based on indirect evidence in previous studies we hypothesize that such agents are liberated gradually from the coating via a cell-mediated degradation. In the present study, we tested this hypothesis by investigating the release mechanism and its kinetics by use of a radiolabeled osteogenic agent (131 I-BMP-2) under conditions in which native cell populations with a coating-degradative potential were either absent or present. The release of 131 I-BMP-2 was monitored for 5 weeks, either in vitro or after implantation at an ectopic (subcutaneous) site in rats in vivo. Only from implants that bore a coating-incorporated depot of bone morphogenetic protein 2 (BMP-2) was the agent released slowly and steadily over 5 weeks, that is, 50% of the loaded dose was liberated in vivo (5 to 10% weekly), as against 14.6% in vitro (less than 1% weekly). The coatings bearing an incorporated depot of BMP-2 underwent significant cell-mediated degradation, whereas under cell-free conditions no degradation occurred, and the spontaneous release of BMP-2 was negligible. Our findings confirm this carrier system to be a suitable vehicle for the sustained and cell-mediated delivery of BMP-2. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A:2363-2371, 2018. more...
- Published
- 2018
- Full Text
- View/download PDF
47. Digitalislike Compounds Restore hNIS Expression and Iodide Uptake Capacity in Anaplastic Thyroid Cancer
- Author
-
Otto C. Boerman, Imke Schuurmans, James Nagarajah, Thomas Crezee, Johannes W. A. Smit, Marika H Tesselaar, Danny Gerrits, Theo S. Plantinga, Ilse van Engen-van Grunsven, and Romana T. Netea-Maier
- Subjects
0301 basic medicine ,Sodium-iodide symporter ,Programmed cell death ,Cell cycle checkpoint ,medicine.medical_treatment ,Rare cancers Radboud Institute for Molecular Life Sciences [Radboudumc 9] ,Thyroid Carcinoma, Anaplastic ,Polymerase Chain Reaction ,Thyroglobulin ,Iodine Radioisotopes ,03 medical and health sciences ,All institutes and research themes of the Radboud University Medical Center ,0302 clinical medicine ,Cell Line, Tumor ,Adenocarcinoma, Follicular ,Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14] ,Autophagy ,medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,Thyroid Neoplasms ,Anaplastic thyroid cancer ,Follicular thyroid cancer ,Cell Proliferation ,Activating Transcription Factor 3 ,Digitalis ,Symporters ,Chemistry ,Gene Expression Profiling ,Cell Cycle ,Thyroid ,Cell Differentiation ,Iodides ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,Microscopy, Fluorescence ,030220 oncology & carcinogenesis ,Cancer research ,Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19] ,Proto-Oncogene Proteins c-fos ,Rare cancers Radboud Institute for Health Sciences [Radboudumc 9] - Abstract
Anaplastic thyroid cancer (ATC) is a rare malignancy that accounts for 1%-2% of all thyroid cancers. ATC is one of the most aggressive human cancers, with rapid growth, tumor invasion, and development of distant metastases. The median survival is only 5 mo, and the 1-y survival is less than 20%. Moreover, as a result of severe dedifferentiation, including the loss of human sodium iodide symporter (hNIS) expression, radioactive iodide (RAI) therapy is ineffective. Recently, we have demonstrated beneficial effects of autophagy-activating digitalislike compounds (DLCs) on redifferentiation and concomitant restoration of iodide uptake in RAI-refractory papillary and follicular thyroid cancer cell lines. In the current study, the effects of DLCs on differentiation and proliferation of ATC cell lines were investigated. Methods: Autophagy activity was assessed in ATC patient tissues by immunofluorescent staining for the autophagy marker microtubule-associated protein 1A/1B-light chain 3 (LC3). In addition, the effect of autophagy-activating DLCs on the proliferation, gene expression profile, and iodide uptake capacity of ATC cell lines was studied. Results: Diminished autophagy activity was observed in ATC tissues, and in vitro treatment of ATC cell lines with DLCs robustly restored hNIS and thyroglobulin expression and iodide uptake capacity. In addition, proliferation was strongly reduced by induction of cell cycle arrest and, to some extent, cell death. Mechanistically, reactivation of functional hNIS expression could be attributed to activation of the transcription factors activating transcription factor 3 and protooncogene c-fosConclusion: DLCs could represent a promising adjunctive therapy for restoring iodide avidity within the full spectrum from RAI-refractory dedifferentiated to ATC. more...
- Published
- 2018
48. Preclinical Evaluation of Ga-DOTA-Minigastrin for the Detection of Cholecystokinin-2/Gastrin Receptor-Positive Tumors
- Author
-
Maarten Brom, Lieke Joosten, Peter Laverman, Wim J.G. Oyen, Martin Béhé, Martin Gotthardt, and Otto C. Boerman
- Subjects
Biology (General) ,QH301-705.5 ,Medical technology ,R855-855.5 - Abstract
In comparison to somatostatin receptor scintigraphy, gastrin receptor scintigraphy using 111 In-DTPA-minigastrin (MG0) showed added value in diagnosing neuroendocrine tumors. We investigated whether the 68 Ga-labeled gastrin analogue DOTA-MG0 is suited for positron emission tomography (PET), which could improve image quality. Targeting of cholecystokinin-2 (CCK 2 )/gastrin receptor-positive tumor cells with DOTA-MG0 labeled with either 111 In or 68 Ga in vitro was investigated using the AR42J rat tumor cell line. Biodistribution was examined in BALB/c nude mice with a subcutaneous AR42J tumor. In vivo PET imaging was performed using a preclinical PET-computed tomographic scanner. DOTA-MG0 showed high receptor affinity in vitro. Biodistribution studies revealed high tumor uptake of 68 Ga-DOTA-MG0: 4.4 ± 1.3 %ID/g at 1 hour postinjection. Coadministration of an excess unlabeled peptide blocked the tumor uptake (0.7 ± 0.1 %ID/g), indicating CCK 2 /gastrin receptor-mediated uptake ( p = .0005). The biodistribution of 68 Ga-DOTA-MG0 was similar to that of 111 In-DOTA-MG0. Subcutaneous and intraperitoneal tumors were clearly visualized by small-animal PET imaging with 5 MBq 68 Ga-DOTA-MG0. 111 In- and 68 Ga-labeled DOTA-MG0 specifically accumulate in CCK 2 /gastrin receptor-positive AR42J tumors with similar biodistribution apart from the kidneys. AR42J tumors were clearly visualized by microPET. Therefore, 68 Ga-DOTA-MG0 is a promising tracer for PET imaging of CCK 2 /gastrin receptor-positive tumors in humans. more...
- Published
- 2011
- Full Text
- View/download PDF
49. Diannexin protects against renal ischemia reperfusion injury and targets phosphatidylserines in ischemic tissue.
- Author
-
Kimberley E Wever, Frank A D T G Wagener, Cathelijne Frielink, Otto C Boerman, Gert J Scheffer, Anthony Allison, Rosalinde Masereeuw, and Gerard A Rongen
- Subjects
Medicine ,Science - Abstract
Renal ischemia/reperfusion injury (IRI) frequently complicates shock, renal transplantation and cardiac and aortic surgery, and has prognostic significance. The translocation of phosphatidylserines to cell surfaces is an important pro-inflammatory signal for cell-stress after IRI. We hypothesized that shielding of exposed phosphatidylserines by the annexin A5 (ANXA5) homodimer Diannexin protects against renal IRI. Protective effects of Diannexin on the kidney were studied in a mouse model of mild renal IRI. Diannexin treatment before renal IRI decreased proximal tubule damage and leukocyte influx, decreased transcription and expression of renal injury markers Neutrophil Gelatinase Associated Lipocalin and Kidney Injury Molecule-1 and improved renal function. A mouse model of ischemic hind limb exercise was used to assess Diannexin biodistribution and targeting. When comparing its biodistribution and elimination to ANXA5, Diannexin was found to have a distinct distribution pattern and longer blood half-life. Diannexin targeted specifically to the ischemic muscle and its affinity exceeded that of ANXA5. Targeting of both proteins was inhibited by pre-treatment with unlabeled ANXA5, suggesting that Diannexin targets specifically to ischemic tissues via phosphatidylserine-binding. This study emphasizes the importance of phosphatidylserine translocation in the pathophysiology of IRI. We show for the first time that Diannexin protects against renal IRI, making it a promising therapeutic tool to prevent IRI in a clinical setting. Our results indicate that Diannexin is a potential new imaging agent for the study of phosphatidylserine-exposing organs in vivo. more...
- Published
- 2011
- Full Text
- View/download PDF
50. Design of Radioiodinated Pharmaceuticals: Structural Features Affecting Metabolic Stability towards in Vivo Deiodination
- Author
-
Lorenzo Cavina, Dion van der Born, Floris P. J. T. Rutjes, Peter H.M. Klaren, Martin C. Feiters, and Otto C. Boerman
- Subjects
0301 basic medicine ,Biodistribution ,Organic Chemistry ,chemistry.chemical_element ,Iodine in biology ,Metabolic stability ,Iodine ,Combinatorial chemistry ,Isotopic labeling ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,chemistry ,In vivo ,030220 oncology & carcinogenesis ,Organic chemistry ,Radionuclide imaging ,Physical and Theoretical Chemistry ,Radioactive iodine - Abstract
Radioiodinated pharmaceuticals are convenient tracers for clinical and research investigations because of the relatively long half-lives of radioactive iodine isotopes (i.e., 123I, 124I, and 131I) and the ease of their chemical insertion. Their application in radionuclide imaging and therapy may, however, be hampered by poor in vivo stability of the C-I bond. After an overview of the use of iodine in biology and nuclear medicine, we present here a survey of the catabolic pathways for iodinated xenobiotics, including their biodistribution, accumulation, and biostability. We summarize successful rational improvements in the biostability and conclude with general guidelines for the design of stable radioiodinated pharmaceuticals. It appears to be necessary to consider the whole molecule, rather than the radioiodinated fragment alone. Iodine radionuclides are generally retained in vivo on sp2 carbon atoms in iodoarenes and iodovinyl moieties, but not in iodinated heterocycles or on sp3 carbon atoms. Iodoarene substituents also have an influence, with increased in vivo deiodination in the cases of iodophenols and iodoanilines, whereas methoxylation and difluorination improve biostability. more...
- Published
- 2017
- Full Text
- View/download PDF
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.