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Biomedical subjects

E Oosterwijk

Publications and source records attributed to E Oosterwijk.

At least 19 recordsLinked to original sources
PubMed2003

Rabbit urethra replacement with a defined biomatrix or small intestinal submucosa.

OBJECTIVE: The evaluation of collagen-based biomatrix (SIS COOK((R))) in comparison to a biochemically reconstructed biomatrix for replacement of the urethra in a rabbit model as a preclinical model. MATERIAL AND METHODS: Rabbits underwent partial urethra replacement (resection of 0.5 to 1.0 cm segment of the urethra), which was replaced with 1 or 4 layers Small Intestinal Submucosa (SIS COOK) patch grafts or with a biochemically defined collagen biomatrix, partly sutured with unresolvable sutures for future reference. Six animals underwent a sham control operation. The grafts of regenerated urethras were harvested at 1, 3 and 9 months after implantation. Urethrography was performed pre-operatively and before sacrificing. The animals were evaluated macroscopically and by routine histology and immunohistochemistry. RESULTS: At 1 month after implantation, the biomatrices (1 layer, 4 layers and our biochemically defined biomatrix) were well distinguishable from the normal surrounding tissues and showed blood vessels at the periphery. Macroscopically, the unresolvable reference sutures were easy to find at all time points. At 3 months the graft was still distinguishable in the 4 layers SIS group. In the 1 layer and the defined biomatrix group a good regeneration of the urethra within the graft was seen with some central fibrosis. Histological and immunohistochemical evaluation showed urothelium regeneration on the 1 layer and on biochemically defined biomatrix with decreasing number of inflammatory cells from 1 month on. In the group treated with 4 layers SIS the urothelium was completely regenerated at 3 months. Histologically, the regeneration of muscle cells in the three biomatrices was comparable. The smooth muscle cells regenerated very slowly as 1 month after implantation no muscle cells were detectable within the grafts. At 3 months a few muscle cells were present in the graft, but cell density did not increase in the following 6 months. Strictures were not observed on control urethrography pre-operatively in the animals. In one case slight narrowing of the urethra on urethrography was seen, but apparently without causing voiding problems. One rabbit developed a fistula near the operation site. CONCLUSION: The biomatrices investigated are feasible scaffolds to repair urethral lesions. The results with our biochemically defined biomatrix are comparable to one layer Small Intestinal Submucosa. Almost no smooth muscle cells population was observed after nine months for the three biomatrices. We conclude that an improved molecularly defined biomatrix focussed on stimulation of smooth muscle cell growth may be necessary to obtain optimal cellular grafting results.

Animals↗
PubMed2002

131 I-cG250 monoclonal antibody immunoscintigraphy versus [18 F]FDG-PET imaging in patients with metastatic renal cell carcinoma: a comparative study.

The aims of this study were to establish the percentage of metastatic renal cell carcinoma (RCC) lesions detected by radioimmunoscintigraphy (RIS) with the chimeric monoclonal antibody 131I-cG250 versus positron emission tomography (PET) with 18F-labelled deoxyglucose ([18F]FDG), and to evaluate the use of these radionuclide imaging modalities compared with routinely used imaging techniques. Twenty patients with metastatic RCC disease were examined with [18F]FDG-PET and 131I-cG250 RIS within 1 week. Total body gamma camera images were obtained up to 120h after injection of 232MBq 131I-cG250. Total body PET scanning was performed 45-60 min after intravenous injection of 370MBq [18F]FDG. Nuclear medicine techniques were compared to routine imaging procedures. Routine imaging modalities revealed a total of 79 metastases. [18F]FDG-PET and 131I-cG250 RIS detected 33 previously unknown metastases, of which 32 were [18F]FDG positive and seven were 131I-cG250 positive. Of the 112 tumour lesions that were documented, [18F]FDG-PET detected 69% (77 out of 112), whereas 131I-cG250 RIS detected only 30% (34 out of 112). In conclusion, [18F]FDG-PET is superior to 131I-cG250 RIS in detecting metastases in patients with metastatic RCC, and therefore seems a promising tool for (re)staging patients with RCC. The usefulness of RIS with a diagnostic dose of 131I-cG250 seems to be restricted to selecting patients for radioimmunotherapy with 131I-cG250.

Aged↗
PubMed2001

Aberrations of the p14(ARF) and p16(INK4a) genes in renal cell carcinomas.

The INK4a / ARF locus on chromosome 9p21, which encodes two distinct genes, p14(ARF) and p16(INK4a), is frequently altered in human neoplasms. To investigate the potential roles of p14(ARF) and p16(INK4a) genes in human renal cell carcinomas (RCCs), we analyzed 6 human RCC cell lines and 91 primary RCCs for homozygous deletion, promoter hypermethylation and expression of the p14(ARF) and p16(INK4a) gene products using differential PCR, methylation-specific PCR, and immunohistochemistry, respectively. Five cell lines showed homozygous co-deletion of both genes and one demonstrated promoter hypermethylation of the p16(INK4a) gene only. Eight of 91 RCCs showed aberrations of p14(ARF) or p16(INK4a) status and six of these featured gross extension into the renal vein. The results suggest that p14(ARF) and p16(INK4a) aberrations may play roles in the relatively late stage of renal tumorigenesis associated with tumor progression.

Carcinoma, Renal Cell↗
PubMed2001

The expression of G250/mn/CA9 antigen by flow cytometry: its possible implication for detection of micrometastatic renal cancer cells.

Monoclonal antibody (mAb) G250 is a well characterized and specific mAb to renal cell carcinoma (RCC). The gene G250 was recently cloned and was proved to be homologous to MN/CA9. The G250/MN/CA9 antigen was recently explored as a potential marker for RCC. Flow cytometry (FCM) allows quantitative analysis of cells. The present study describes a flow cytometric method to detect this antigen in human cell lines and in malignant and normal renal tissues. Twelve human carcinoma cell lines (HeLa, Colo205, HT29, BxPC3, OVCAR3, SKOV3, ACHN, A704, CAKI-2, SKRC-59, SKRC-10, and SKRC-52), 10 specimens of normal peripheral blood mononuclear cells, and 38 malignant and 36 adjacent normal renal tissues were studied. The malignant and normal renal tissues were disaggregated mechanically into a single-cell suspension, stained by mAb G250, and analyzed by FCM. All 22 of the clear cell carcinomas, 6 of 8 mixed cell carcinomas, and 3 of 6 granular cell carcinomas were positive for G250/MN/CA9 antigen. SKRC-52 and SKRC-10 were strongly positive for G250/ MN/CA9. The G250/MN/CA9 antigen could also be detected in HeLa, SKOV3, HT29, and A704 cells. One chromophobic, one chromophilic cell carcinoma, the normal renal tissues, and normal peripheral blood mononuclear cells were considered as negative. Our results further confirmed that the G250/MN/CA9 antigen was an ideal marker for RCC, especially for clear cell carcinomas, and that this antigen was present in several types of malignant cells. FCM may serve as a fast tool of immunocytochemical detection of renal cancer cells. Flow cytometric detection of renal cancer cells by using mAb G250 should be further explored.

Adult↗
PubMed2000

Molecular cloning and immunogenicity of renal cell carcinoma-associated antigen G250.

The molecular cloning of the cDNA and gene encoding the renal cell carcinoma (RCC)-associated protein G250 is described. This protein is one of the best markers for clear cell RCC: all clear-cell RCC express this protein, whereas no expression can be detected in normal kidney and most other normal tissue. Antibody studies have indicated that this molecule might serve as a therapeutic target. In view of the induction/up-regulation of G250 antigen in RCC, its restricted tissue expression and its possible role in therapy, we set out to molecularly define the G250 antigen, which we identified as a transmembrane protein identical to the tumor-associated antigen MN/CAIX. We determined, by FISH analysis, that the G250/MN/CAIX gene is located on chromosome 9p12-13. In view of the relative immunogenicity of RCC, we investigated whether the G250 antigen can be recognized by TIL derived from RCC patients. The initial characterization of 18 different TIL cultures suggests that anti-G250 reactivity is rare.

Antigens, Neoplasm↗
PubMed2000

Alterations in expression of cadherin-6 and E-cadherin during kidney development and in renal cell carcinoma.

OBJECTIVES: Cell-cell adhesion mediated by cadherins is tight and stable and preserves tissue integrity. However, during tissue remodeling, e.g., development, adhesion may be modified for morphogenic movement. Similarly, during carcinogenesis, cell-cell adhesion might alter leading to a more aggressive phenotype. Here we describe cadherin expression patterns in developing, adult, and neoplastic kidney. METHODS: Fetal kidneys were obtained from voluntary terminations of pregnancy and 43 renal cell carcinomas (RCC) and normal kidneys were obtained at nephrectomy. Frozen sections of these specimens were stained immunohistochemically using antibodies against E-cadherin (ECD), cadherin-6 (CAD6) and alpha-catenin (alpha-cat). RESULTS: CAD6 was expressed in lower and middle limbs of the S-shaped bodies, structures that will develop into renal proximal tubules, which also express CAD6. Similarly, ECD was expressed in the upper limb of S-shaped bodies, structures which will develop into distal and collecting tubules which also express ECD. Twenty-four out of 43 RCC (55.8%) displayed a CAD6 (+)/ECD (-)/alpha-cat (+) phenotype. The other RCC had a CAD6 (+)/ECD (+)/alpha-cat (+) phenotype (10/43, 23.2%), CAD6 (-)/ECD (+)/alpha-cat (+) phenotype (3/43, 7.0%) or CAD6 (-)/ECD (-)/alpha-cat (+) phenotype (6/43, 14.0%), respectively. On the other hand, normal, heterogeneous, or absent expression of CAD6 was seen in 19, 15, and 9 tumors, whereas in 11, 2, and 30 tumors, respectively, ECD expression was seen. Survival curves showed that abnormal CAD6 expression correlated with a poor prognosis rather than abnormal ECD expression. CONCLUSIONS: The combination of cadherin expression appeared to be fixed relatively early during kidney organogenesis. Since almost all RCC originate from proximal tubular epithelial cells (CAD6 (+)/ECD (-)/alpha-cat (+)), only 55. 8% of RCC retained the original cadherin phenotype. Alterations in expression of these molecules may be a reflection of the degree of dedifferentiation from the primary organ. In addition, scoring of expression patterns including heterogeneous expression could be a useful tool to estimate the malignancy potential of the tumor.

Cadherins↗
PubMed1999

The renal cell carcinoma-associated antigen G250 encodes a human leukocyte antigen (HLA)-A2.1-restricted epitope recognized by cytotoxic T lymphocytes.

Evidence has accumulated that the immune system can play a significant role in the defense against tumors in humans. Especially melanoma and renal cell carcinoma (RCC) are considered immunogenic tumors. In contrast to melanoma, hardly any RCC-associated antigens have been identified as targets for RCC-reactive T cells. Here, we report the identification of a human leukocyte antigen (HLA)-A2.1-restricted T-cell epitope within the G250 antigen. This antigen is expressed in 85% of RCCs but not by neighboring normal kidney tissue and has recently been molecularly defined and shown to be identical to MN/CA IX. Computer-aided motif prediction revealed the presence of 60 potential HLA-A2.1-binding peptides within the G250 antigen. Subsequent binding analysis showed that 13 of these peptides bound to HLA-A2.1 with high-to-intermediate affinity. Analysis of their immunogenicity in HLA-A2.1Kb transgenic mice indicated that 4 of the 13 peptides gave rise to cytotoxic T lymphocytes (CTLs) capable of lysing peptide-loaded target cells. However, only the G250 peptide 254-262 induced CTLs that recognized target cells that endogenously expressed the G250 antigen. Similarly, we were also able to raise human CTLs against the G250 peptide 254-262, which lysed target cells that endogenously expressed the G250 antigen. These findings and the high prevalence of this antigen in RCC patients makes G250 a potential target for anti-RCC immunotherapy.

Animals↗
PubMed1999

Pretargeting of renal cell carcinoma: improved tumor targeting with a bivalent chelate.

Radiolabeled monoclonal antibodies (mAbs) can target tumors selectively. Sustained activity levels in nontarget tissues limit their application. Pretargeting approaches using bispecific mAbs (bsmAbs) or the biotinavidin interaction have been proposed to improve tumor:nontumor ratios. Pretargeting a tumor and subsequently administering the radioactivity as a low molecular weight ligand fundamentally changes the pharmacokinetics of the radiolabel. In previous studies, we have shown successful radioimmunotargeting of diethylenetriaminepentaacetic acid (DTPA) labeled with indium-111 to renal cell carcinoma (RCC) after pretargeting in nude mice. In this study, we aimed to optimize further a pretargeting strategy in nude mice with RCC xenografts based on a bispecific anti-RCC x anti-DTPA mAb. Using this two-step approach, we studied whether the use of a bivalent chelate ((111)In-diDTPA) could improve radioimmunotargeting. The (111)In-diDTPA dose greatly affected the uptake of the radiolabeled chelate in the tumor. At a low (111)In-diDTPA dose (< or = 7 pmol), tumor uptake of (111)In-diDTPA was very high [>50% injected dose (ID)/g, 1 h postinjection (p.i.)], whereas at higher doses (> or = 20 pmol), tumor uptake of (111)In-diDTPA decreased (<30% ID/g). With monovalent (111)In-DTPA uptake of the radiolabel in the tumor was much lower (<10% ID/g, 1 h p.i.). Furthermore, the bivalent chelate accreted rapidly in the tumor (78% ID/g, 4 h p.i.) and was virtually completely retained in the tumor during several days p.i. (92% ID/g, 72 h p.i.). Clearance of the (111)In-diDTPA from the blood and kidneys was rapid and complete without the need to clear the bsmAb from the blood, probably due to the relative lability of the univalent bsmAb-diDTPA complexes in the blood. As a result, with this two-step pretargeting approach tumor:blood ratios increased up to values as high as 3500 at 72 h p.i. High doses of diDTPA could be targeted preferentially to the tumor, indicating that this approach could also be used for radioimmunotherapy. Tumors could be imaged up to 1 week p.i. of 50 microCi of (111)In-diDTPA. Quantitative analysis of the images confirmed the biodistribution data and indicated that, at 20 h p.i., 50 +/- 15% of the whole-body activity was localized in the tumor. In conclusion, these studies indicate that the use of bivalent chelates can very effectively optimize two-step targeting of tumors with bsmAbs. Our data indicate that this approach could optimize radioimmunotherapy.

Animals↗
PubMed1999

Intratumoral distribution of two consecutive injections of chimeric antibody G250 in primary renal cell carcinoma: implications for fractionated dose radioimmunotherapy.

Tumor uptake of the chimeric G250 (cG250) monoclonal antibody (mAb) in patients with primary renal cell carcinoma (RCC) is among the highest reported in solid tumors. However, as observed in other tumor types, the intratumoral distribution of the antibody is highly heterogeneous, which may limit the efficacy of radioimmunotherapy. A number of highly dynamic physiological factors have been postulated that may contribute to heterogeneous tumor uptake of antibodies. Their impact on tumor uptake of antibodies may vary from one tumor region to another as well as from one day to the next. Here, we report on a clinical study that was designed to investigate whether the pattern of mAb cG250 uptake within RCC tumors is altered with subsequent injections. Ten patients with a clinical diagnosis of primary RCC were studied. Nine days before surgery, patients received 125I-cG250 (5 mg of cG250, 50 microCi of 125I), followed by a second injection of 131I-cG250 (5 mg of cG250, 3.5 mCi of 131I) 4 days later. Postsurgery, the tumor was cut into (1-cm) thick slices. Slices were imaged on a gamma camera, and the slice with the most pronounced heterogeneity in 131I-cG250 distribution was selected and cut into 1-cm3 cubes. Each cube was analyzed for 121I-cG250 and 131I-cG250 uptake, and the 131I/125I ratio was determined. For each tumor slice, the distribution patterns of both isotopes were reconstructed and compared with each other. All tumors analyzed showed a heterogeneous distribution of both isotopes throughout the tumor slice; focal uptake in some areas of a tumor reached very high levels (up to 0.19% injected dose/g), whereas other tumorous areas of the same slice showed much lower uptake (as low as 0.0047% injected dose/g). Remarkably, in all tumors, the distribution pattern of both injections was identical: without exception, in all samples analyzed (n = 692), the uptake of 125I-cG250 was similar to 131I-cG250 uptake. Overall, the 131I/125I ratio was 1.64+/-0.31 (mean+/-SD). The constant 131I/125I ratios, observed in all tumor samples investigated, indicate that the tumor parameters governing cG250 mAb uptake were not altered significantly within the time period studied. In addition, the results of this study suggest that multiple radiolabeled antibody injections, administered within short time periods, will target the same areas within a tumor and, thus, will not solve the problem of heterogeneous tumor uptake of antibody.

Adult↗
PubMed1999

MN/CA IX/G250 as a potential target for immunotherapy of renal cell carcinomas.

The monoclonal antibody G250 (mAbG250) raised against a human renal cell carcinoma (RCC) has been shown to react with a large number of RCCs. Recently, G250 antigen was isolated and found to be homologous to the MN/CA9 gene originally identified in HeLa cells. To determine whether G250 antigen (MN/CA IX/G250) could be a potential therapeutic target and a tumour marker, a total of 147 cases of RCC were investigated immunohistochemically as well as by reverse transcriptase polymerase chain reaction (RT-PCR) analysis. In addition, total RNAs extracted from patients' peripheral blood samples were analysed for MN/CA9/G250 mRNA signals. Immunohistochemistry demonstrated strong expression in 128/147 (87.1%) of RCCs, in contrast to the lack of expression observed in normal tissues. RT-PCR analyses of frozen specimens resulted in the clear detection of MN/CA9/G250 mRNA signals in 137/147 (93.2%), and despite subtle differences the results were almost identical to those for immunohistochemistry. Although high-grade and -stage tumours exhibited significantly lower expression than low-grade and -stage tumours, a large proportion of tumours expressed MN/G250 protein as well as mRNA. RT-PCR analysis of patients' blood samples revealed the presence of circulating MN/CA9/G250 expressing cells. These findings suggest that this antigen may be a potential therapeutic target as well as diagnostic marker for RCCs.

Antigens, Neoplasm↗
PubMed1999

In vivo and in vitro characterizations of three 99mTc-labeled monoclonal antibody G250 preparations.

UNLABELLED: In previous clinical studies, excellent visualization of tumor lesions has been observed with 131I-labeled monoclonal antibody (mAb) G250 in patients with renal cell carcinoma (RCC). In several cases, 131I-cG250 immunoscintigraphy disclosed tumor lesions that were not visualized by radiography or CT. To improve image quality, we aimed to develop a 99mTc-labeled mAb G250 preparation for radioimmunodetection of RCC. We studied in vitro stability, biodistribution and imaging potential of three 99mTc-labeled G250 preparations in nude mice with subcutaneous RCC xenografts.125I-G250 and the nonspecific mAb 131I-MN14 were used as control antibodies. METHODS: The mAb G250 was labeled with 99mTc according to three methods using: (a) S-hydrazinonicotinamide (HYNIC), (b) S-benzoylmercaptoacetyltriglycine (MAG3) and (c) a direct labeling method (Schwarz method). The stability of all preparations was tested in serum at 37 degrees C during 48 h. In addition, diethylenetriamine pentaacetic acid, cysteine and glutathione challenge assays were performed. RESULTS: All preparations showed good stability in serum during the 48-h incubation period. 99mTc-G250 (Schwarz) showed release of the radiolabel at a 100-fold or higher molar excess of cysteine and at a 10,000-fold or higher molar excess of glutathione. 99mTc-MAG3-G250 showed release of the radiolabel at a 10,000-fold molar excess of cysteine. 99mTc-HYNIC-G250 was stable under all conditions. Tumors were clearly visualized with all preparations. 99mTc-G250 (Schwarz) showed significantly lower blood levels (3.8 %ID/g) compared with all other preparations (11.2, 13.4 and 13.4 %ID/g for 99mTc-HYNIC-G250, 99mTc-MAG3-G250 and 125I-G250, respectively, 48 h postinjection). At 48-h postinjection, mean tumor uptake was very high with all mAb G250 preparations: 92.4 (99mTc-HYNIC-G250), 125.9 (99mTc-MAG3-G250), 29.4 (99mTc-G250 Schwarz) and 75.4 (125I-G250) %ID/g. Mean tumor uptake of the nonspecific 131I-MN14 mAb was 6.6 %ID/g. CONCLUSION: In this study, 99mTc-HYNIC-G250 showed excellent in vitro stability and tumor targeting. Moreover, this preparation could be labeled with high efficiency (>95%) at room temperature within 15 min. Therefore, 99mTc-HYNIC-G250 seems to be an ideal candidate for radioimmunodetection of RCC.

Animals↗
PubMed1999

Phase I radioimmunotherapy of metastatic renal cell carcinoma with 131I-labeled chimeric monoclonal antibody G250.

Clinical tumor targeting studies with chimeric monoclonal antibody G250 (cG250) in renal cell carcinoma (RCC) patients indicated the potential use of this antibody for radioimmunotherapy. Here we report on a phase I activity dose escalation study to determine the safety, the maximum tolerable dose (MTD), and the possible therapeutic potential of 131I-labeled cG250 in patients with progressive metastatic RCC. All patients (n = 12) received a diagnostic i.v. infusion of 5 mg of cG250 labeled with 222 MBq of 131I. If accumulation of the antibody in metastatic lesions was observed, patients were hospitalized and a second, therapeutic, i.v. infusion of 5 mg of cG250 labeled with a high dose of 131I was administered (n = 8). Three patients per dose level were entered, starting at 1665 MBq/m2. If no dose-limiting toxicity occurred, the study continued at the next dose level (555 MBq/m2 increase). Most patients experienced mild nausea without vomiting. No other complaints were reported during hospitalization. In two of two patients who received a dose of 2775 MBq/m2, grade IV hematological toxicity was observed, which was defined as dose limiting. Thus, the MTD was set at 2220 MBq/m2. In one patient (2220 MBq/m2), stable disease (lasting 3-6 months) was achieved, whereas another patient (2220 MBq/m2) showed a partial response that is ongoing (>9 months). The minor responses observed in this phase I trial in patients with an advanced stage of RCC are encouraging and warrant further study in a phase II setting at the MTD to determine the efficacy of radioimmunotherapy for metastatic RCC.

Adult↗
PubMed1998

Two-step radio-immunotargeting of renal-cell carcinoma xenografts in nude mice with anti-renal-cell-carcinoma X anti-DTPA bispecific monoclonal antibodies.

The specificity of antibodies offers unique opportunities to target tumors with radionuclides. However, due to the slow clearance of radiolabeled antibody, relatively high back-ground is observed in non-target organs. Pre-targeting protocols using bispecific monoclonal antibodies (bsMAbs) and radiolabeled chelates may overcome this problem. We have evaluated the anti-renal-cell-carcinoma (RCC) X anti-DTPA bsMAb G250 x DTIn1 for 2-step targeting of RCC tumors in nude mice. Tumor uptake of 111In-DTPA was similar up to a 3-day interval between bsMAb and 111In-DTPA injections and decreased thereafter. The effect of G250 x DTIn1 protein dose was studied. High tumor uptake was seen at 1 to 4 micrograms, whereas at higher doses uptake decreased. Tumor was saturated with 15 micrograms bsMAb. At the saturating bsMAb dose the 111In-DTPA amount was varied. High tumor uptake was observed at a 10-fold molar excess 111In-DTPA, whereas at higher excess uptake decreased. After priming with 15 micrograms bsMAb and targeting with a 10-fold molar excess 111In-DTPA, the biodistribution of 111In-DTPA was studied for 1 to 48 hr after injection. Good tumor retention of 111In-DTPA was observed, while the radiolabel cleared rapidly from the blood. Consequently, tumor-to-blood ratios increased with time to 500 at 24 hr after injection. In conclusion, RCC xenografts can be targeted efficiently using G250 x DTIn1 and 111In-DTPA. However, this requires careful tuning of bsMAb protein dose and 111In-DTPA dose. Using the optimal protein dose and 111In-DTPA dose, high 111In-DTPA tumor uptake and tumor-to-blood ratios can be obtained, thus providing good perspectives for diagnostic and therapeutic use in humans.

Animals↗
PubMed1998

Immunohistochemical analysis of intratumoral heterogeneity of [131I]cG250 antibody uptake in primary renal cell carcinomas.

In previous studies, highly heterogeneous uptake of 131I-labelled chimeric monoclonal antibody G250 ([131I]cG250) in primary renal cell carcinomas has been observed (intratumoral differences > factor 100). In this study, we investigated a possible correlation between intratumoral antibody uptake and four immunohistochemically determined parameters: G250 antigen expression, blood vessel density, neovascularization and percentage of viable tumour cells. Whole tumour slices of four different tumours were cut into 1-cm3 cubes, and in each cube the [131I]cG250 uptake was determined. The correlation between [131I]cG250 uptake and each individual parameter was determined in a multiple regression analysis. Additionally, the data were reanalysed after introducing arbitrary cut-off values for each parameter. If a sample showed expression of a parameter above the introduced threshold value, this sample fulfilled one condition. Subsequently, the Pearson correlation coefficients were calculated from [131I]cG250 uptake and the number of fulfilled conditions (0-3). All tumour samples with high [131I]cG250 uptake [> 0.1% of the injected dose per gram (ID g(-1))] showed high antigen expression (> 50%). However, not all samples with high antigen expression displayed high uptake. A statistically significant correlation between [131I]cG250 uptake and antigen expression was found (beta = 0.44, 0.69 and 0.74) in three out of four tumours analysed. Of the other determined parameters, no consistent correlation with [131I]cG250 uptake was found; only the percentage of viable tumour cells correlated significantly in two out of four tumours (beta = 0.80 and 0.26). Calculation of the Pearson correlation coefficients showed a statistically significant correlation between [131I]cG250 uptake and an increased number of fulfilled conditions in all tumours, indicating that each of the individual parameters contribute to the uptake of [131I]cG250. These observations indicate that high antigen expression is a prerequisite for high antibody uptake. However, regional differences in antibody uptake within a tumour cannot be explained by antigen expression alone.

Antibodies, Monoclonal↗
PubMed1998

Tumor retention of 186Re-MAG3, 111In-DTPA and 125I labeled monoclonal antibody G250 in nude mice with renal cell carcinoma xenografts.

UNLABELLED: In radioimmunotherapy of solid tumors substantial gain might be achieved by carefully selecting the radionuclide and the linker connecting it to the antibody. In contrast to 131I, radiometals such as 90Y and 111In may be retained in the tumor cell after internalization of the antibody, thereby enhancing the radiation dose to the tumor. The physical properties of 186Re with 1.08 MeV beta-emission (71%) and 137 keV gamma-emission (10%) seem ideal for radioimmunotherapy. In this study we investigated in nude mice with s.c. renal cell carcinoma xenografts the biodistribution and the retention in the tumor of 186Re-MAG3 labeled monoclonal antibody (mAb) G250 as compared to 111In-DTPA-G250, to 125I-G250 and to 131I-MN14 (non-specific control mAb). Radiolabeled antibody preparations were i.v. injected. Seventy two hours p.i. the biodistribution of the radiolabel was determined. Blood levels of all mAb G250 preparations were remarkably low (mean: 2.38, 1.40 and 1.43% ID/g for 125I, 111In and 186Re respectively) whereas blood levels of mAb MN14 were significantly higher (mean: 12.3% ID/g), indicating tumor processing of mAb G250. Retention of 111In in the tumor was significantly higher than of 186Re and 125I whereas retention in the tumor of 186Re and 125I did not differ significantly. CONCLUSION: In contrast to other radiometals such as 111In and 90Y, 186Re is not retained in the tumor cell. Therefore 186Re has no additional advantage for radioimmunotherapy with respect to retention in the tumor.

Animals↗