In this study, we compared the tumor-targeting properties, therapeutic efficacy, and tolerability... more In this study, we compared the tumor-targeting properties, therapeutic efficacy, and tolerability of the humanized anti-CAIX antibody (hG250) labeled with either the α-emitter actinium-225 (225Ac) or the β--emitter lutetium-177 (177Lu) in mice. BALB/c nude mice were grafted with human renal cell carcinoma SK-RC-52 cells and intravenously injected with 30 µg [225Ac] Ac-DOTA-hG250 (225Ac-hG250) or 30 µg [177Lu] Lu-DOTA-hG250 (177Lu-hG250), followed by ex vivo biodistribution studies. Therapeutic efficacy was evaluated in mice receiving 5, 15, and 25 kBq of 225Ac-hG250; 13 MBq of 177Lu-hG250; or no treatment. Tolerability was evaluated in non-tumor-bearing animals. High tumor uptake of both radioimmunoconjugates was observed and increased up to day 7 (212.8 ± 50.2 %IA/g vs. 101.0 ± 18.4 %IA/g for 225Ac-hG250 and 177Lu-hG250, respectively). Survival was significantly prolonged in mice treated with 15 kBq 225Ac-hG250, 25 kBq 225Ac-hG250, and 13 MBq 177Lu-hG250 compared to untreated contr...
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 2005
We have developed an efficient pretargeting strategy for renal cell carcinoma (RCC) based on a bi... more We have developed an efficient pretargeting strategy for renal cell carcinoma (RCC) based on a biologically produced bispecific monoclonal antibody (bs-mAb). Tumor targeting with this 2-step pretargeting strategy in the NU-12 mouse RCC model was very efficient compared with other pretargeting strategies, possibly due to unique characteristics of the NU-12 tumor used in our studies. Here we describe the bs-mAb G250xDTIn-1 pretargeting strategy in 3 different RCC nude mouse models. Three different human RCC xenografts in nude mice (NU-12, SK-RC-1, and SK-RC-52 tumors) were pretargeted with 100 pmol bs-mAb G250xDTIn-1. Three days after administration of the bs-mAb, mice were injected intravenously with 4 pmol 111In-labeled bivalent peptide, diDTPA-FKYK (DTPA is diethylenetriaminepentaacetic acid). At 1, 4, 24, 48, and 72 h after injection of the radiolabeled peptide, the biodistribution of the radiolabel was determined. The 3 RCC tumors were characterized in vivo and in vitro for G250 ...
Repair of long ureteral defects often requires long graft tissues and extensive surgery. This is ... more Repair of long ureteral defects often requires long graft tissues and extensive surgery. This is associated with complications, including a lack of suitable tissue and graft site morbidity. Tissue engineering may provide an attractive alternative to the autologous graft tissues. In this study, ureteral repair using (preimplanted) tubular collagen-Vicryl templates was evaluated in a new goat model. Tubular templates were prepared from tubularized Vicryl meshes and 0.7% type-I collagen (length = 6 cm, inner diameter = 6 mm, wall thickness = 3 mm). In total, twelve goats were used and evaluated after 3 months. Eight goats were implanted with the collagen-Vicryl templates and in four goats the templates were first preimplanted in the subcutis and subsequently used as ureteral graft. Template implantation was successful in 92% of the goats(11/12). During follow-up, 82% of the animals (9/11) survived without signs of discomfort. Two animals were sacrificed prematurely due to kidney perfor...
The influence of high energy shock waves (HESW) on the local concentration of systemically given ... more The influence of high energy shock waves (HESW) on the local concentration of systemically given TNF-alpha was studied in a syngeneic rat bladder tumor model. 125I-TNF-alpha was injected intravenously and within 1 minute was followed by HESW tumor exposure. High energy shock waves were generated using an experimental shock wave emitter based on the Siemens Lithostar Plus. Administration of HESW to RBT323 tumors resulted in a 3-fold increase in uptake of 125I-TNF-alpha in the tumor compared with nontreated tumors, whereas the tissue distribution and pharmacokinetics of nontumor tissue were similar irrespective of HESW exposure. These results demonstrate that HESW administration leads to an increase in the local concentration of a systemically given drug. The capacity of HESW to increase local drug concentrations will be of importance in designing more effective combined treatment strategies.
Renal cell carcinoma (RCC) is characterized by an unpredictable clinical course. Therefore, progn... more Renal cell carcinoma (RCC) is characterized by an unpredictable clinical course. Therefore, prognostic factors are urgently needed. So far, clinical staging is the most powerful predictor of the progression of RCC. A better understanding of cell biological and molecular changes associated with the development of this disease is urgently needed. Recently, application of a number of these have been tested. Whereas some do not seem to have prognostic value over the available classical prognostic markers, quantitative nuclear morphometric measurement and assessment of cadherin-mediated adhesion complexes (catenin immunohistochemistry) have opened new prospectives.
Four mouse monoclonal antibodies reacting with renal proximal epithelium were characterized on no... more Four mouse monoclonal antibodies reacting with renal proximal epithelium were characterized on normal adult tissues, fetal kidneys, and various malignancies. These four antibodies were found to react with renal cell carcinomas (RCCs) but not with a variety of other tumors. Three antibodies react only with some primary RCCs and not with metastatic RCCs. The fourth antibody, RC 38, reacts with 46 of 47 primary RCCs tested and with 8 of 13 RCC metastases. No reaction was seen with 179 tumors of various origin, which indicates that this antibody is very useful in diagnosing RCC.
The maturation state of (monocyte-derived) dendritic cells (DCs) determines the type of T-cell re... more The maturation state of (monocyte-derived) dendritic cells (DCs) determines the type of T-cell response. Currently, several maturation cocktails are used in clinical trials, most commonly a cocktail of TNF-alpha, PGE2, IL-1beta, and IL-6. The authors studied DC phenotype and functional ability to stimulate TH1 responses after maturation with different cocktails employing clinically approved agents. DCs were stimulated with the microbial agent Ribomunyl combined with IFN-gamma and various inflammatory cytokine cocktails: TNF-alpha/IL-1beta/IFN-gamma and TNF-alpha/PGE2 combined with monocyte-conditioned medium (MCM) or IL-1beta/IL-6. Regardless of the maturation cocktail used, all DCs possessed the characteristic phenotype of mature, migratory DCs (high expression of CD40, CD80, CD83, CD86, CCR7, MHC class I and MHC class II). Ribomunyl/IFN-gamma matured DCs produced high IL-12p70 levels, whereas other maturation stimuli did not. Even more striking, restimulation of Ribomunyl IFN-gamma mDCs with CD40-activating antibody reactivated IL-12p70 production. No IL-12p70 could be detected when DCs were stimulated with TNF-alpha/PGE2 combined with MCM or IL-1beta/IL-6, presumably by suppression by PGE2. Restimulation of these DCs with CD40-activating antibody failed to activate IL-12p70 production. Moreover, low levels of IL-10 were observed, possibly indicating inhibition of TH1-cell responses. Indeed, T cells stimulated with these DCs produced high levels of type 2 cytokine IL-5 and outgrowth of CD4CD25 T cells. This study shows that DC maturation with cytokine cocktails different from those most commonly used could be beneficial for immunotherapy trials in cancer patients.
In this study, we compared the tumor-targeting properties, therapeutic efficacy, and tolerability... more In this study, we compared the tumor-targeting properties, therapeutic efficacy, and tolerability of the humanized anti-CAIX antibody (hG250) labeled with either the α-emitter actinium-225 (225Ac) or the β--emitter lutetium-177 (177Lu) in mice. BALB/c nude mice were grafted with human renal cell carcinoma SK-RC-52 cells and intravenously injected with 30 µg [225Ac] Ac-DOTA-hG250 (225Ac-hG250) or 30 µg [177Lu] Lu-DOTA-hG250 (177Lu-hG250), followed by ex vivo biodistribution studies. Therapeutic efficacy was evaluated in mice receiving 5, 15, and 25 kBq of 225Ac-hG250; 13 MBq of 177Lu-hG250; or no treatment. Tolerability was evaluated in non-tumor-bearing animals. High tumor uptake of both radioimmunoconjugates was observed and increased up to day 7 (212.8 ± 50.2 %IA/g vs. 101.0 ± 18.4 %IA/g for 225Ac-hG250 and 177Lu-hG250, respectively). Survival was significantly prolonged in mice treated with 15 kBq 225Ac-hG250, 25 kBq 225Ac-hG250, and 13 MBq 177Lu-hG250 compared to untreated contr...
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 2005
We have developed an efficient pretargeting strategy for renal cell carcinoma (RCC) based on a bi... more We have developed an efficient pretargeting strategy for renal cell carcinoma (RCC) based on a biologically produced bispecific monoclonal antibody (bs-mAb). Tumor targeting with this 2-step pretargeting strategy in the NU-12 mouse RCC model was very efficient compared with other pretargeting strategies, possibly due to unique characteristics of the NU-12 tumor used in our studies. Here we describe the bs-mAb G250xDTIn-1 pretargeting strategy in 3 different RCC nude mouse models. Three different human RCC xenografts in nude mice (NU-12, SK-RC-1, and SK-RC-52 tumors) were pretargeted with 100 pmol bs-mAb G250xDTIn-1. Three days after administration of the bs-mAb, mice were injected intravenously with 4 pmol 111In-labeled bivalent peptide, diDTPA-FKYK (DTPA is diethylenetriaminepentaacetic acid). At 1, 4, 24, 48, and 72 h after injection of the radiolabeled peptide, the biodistribution of the radiolabel was determined. The 3 RCC tumors were characterized in vivo and in vitro for G250 ...
Repair of long ureteral defects often requires long graft tissues and extensive surgery. This is ... more Repair of long ureteral defects often requires long graft tissues and extensive surgery. This is associated with complications, including a lack of suitable tissue and graft site morbidity. Tissue engineering may provide an attractive alternative to the autologous graft tissues. In this study, ureteral repair using (preimplanted) tubular collagen-Vicryl templates was evaluated in a new goat model. Tubular templates were prepared from tubularized Vicryl meshes and 0.7% type-I collagen (length = 6 cm, inner diameter = 6 mm, wall thickness = 3 mm). In total, twelve goats were used and evaluated after 3 months. Eight goats were implanted with the collagen-Vicryl templates and in four goats the templates were first preimplanted in the subcutis and subsequently used as ureteral graft. Template implantation was successful in 92% of the goats(11/12). During follow-up, 82% of the animals (9/11) survived without signs of discomfort. Two animals were sacrificed prematurely due to kidney perfor...
The influence of high energy shock waves (HESW) on the local concentration of systemically given ... more The influence of high energy shock waves (HESW) on the local concentration of systemically given TNF-alpha was studied in a syngeneic rat bladder tumor model. 125I-TNF-alpha was injected intravenously and within 1 minute was followed by HESW tumor exposure. High energy shock waves were generated using an experimental shock wave emitter based on the Siemens Lithostar Plus. Administration of HESW to RBT323 tumors resulted in a 3-fold increase in uptake of 125I-TNF-alpha in the tumor compared with nontreated tumors, whereas the tissue distribution and pharmacokinetics of nontumor tissue were similar irrespective of HESW exposure. These results demonstrate that HESW administration leads to an increase in the local concentration of a systemically given drug. The capacity of HESW to increase local drug concentrations will be of importance in designing more effective combined treatment strategies.
Renal cell carcinoma (RCC) is characterized by an unpredictable clinical course. Therefore, progn... more Renal cell carcinoma (RCC) is characterized by an unpredictable clinical course. Therefore, prognostic factors are urgently needed. So far, clinical staging is the most powerful predictor of the progression of RCC. A better understanding of cell biological and molecular changes associated with the development of this disease is urgently needed. Recently, application of a number of these have been tested. Whereas some do not seem to have prognostic value over the available classical prognostic markers, quantitative nuclear morphometric measurement and assessment of cadherin-mediated adhesion complexes (catenin immunohistochemistry) have opened new prospectives.
Four mouse monoclonal antibodies reacting with renal proximal epithelium were characterized on no... more Four mouse monoclonal antibodies reacting with renal proximal epithelium were characterized on normal adult tissues, fetal kidneys, and various malignancies. These four antibodies were found to react with renal cell carcinomas (RCCs) but not with a variety of other tumors. Three antibodies react only with some primary RCCs and not with metastatic RCCs. The fourth antibody, RC 38, reacts with 46 of 47 primary RCCs tested and with 8 of 13 RCC metastases. No reaction was seen with 179 tumors of various origin, which indicates that this antibody is very useful in diagnosing RCC.
The maturation state of (monocyte-derived) dendritic cells (DCs) determines the type of T-cell re... more The maturation state of (monocyte-derived) dendritic cells (DCs) determines the type of T-cell response. Currently, several maturation cocktails are used in clinical trials, most commonly a cocktail of TNF-alpha, PGE2, IL-1beta, and IL-6. The authors studied DC phenotype and functional ability to stimulate TH1 responses after maturation with different cocktails employing clinically approved agents. DCs were stimulated with the microbial agent Ribomunyl combined with IFN-gamma and various inflammatory cytokine cocktails: TNF-alpha/IL-1beta/IFN-gamma and TNF-alpha/PGE2 combined with monocyte-conditioned medium (MCM) or IL-1beta/IL-6. Regardless of the maturation cocktail used, all DCs possessed the characteristic phenotype of mature, migratory DCs (high expression of CD40, CD80, CD83, CD86, CCR7, MHC class I and MHC class II). Ribomunyl/IFN-gamma matured DCs produced high IL-12p70 levels, whereas other maturation stimuli did not. Even more striking, restimulation of Ribomunyl IFN-gamma mDCs with CD40-activating antibody reactivated IL-12p70 production. No IL-12p70 could be detected when DCs were stimulated with TNF-alpha/PGE2 combined with MCM or IL-1beta/IL-6, presumably by suppression by PGE2. Restimulation of these DCs with CD40-activating antibody failed to activate IL-12p70 production. Moreover, low levels of IL-10 were observed, possibly indicating inhibition of TH1-cell responses. Indeed, T cells stimulated with these DCs produced high levels of type 2 cytokine IL-5 and outgrowth of CD4CD25 T cells. This study shows that DC maturation with cytokine cocktails different from those most commonly used could be beneficial for immunotherapy trials in cancer patients.
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Papers by Egbert Oosterwijk