Radiation dosimetry for 90Y-2IT-BAD-Lym-1 extrapolated from pharmacokinetics using 111In-2IT-BAD-Lym-1 in patients with non-Hodgkin's lymphoma.
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Several monoclonal antibodies, including Lym-1, have proven effective for treatment of hematologic malignancies. Lym-1, which preferentially targets malignant lymphocytes, has induced therapeutic responses and prolonged survival in patients with non-Hodgkin's lymphoma (NHL) when labeled with 131. Because radiometal-labeled monoclonal antibodies provide higher tumor radiation doses than corresponding 131I-labeled monoclonal antibodies, the radiation dosimetry of 90Y-2-iminothiolane-2-[p-(bromoacetamido)benzyl]-1,4,7,10-tetraazacyc lododecane-N,N',N",N"'-tetraacetic acid-Lym-1 (90Y-21T-BAD-Lym-1) is of importance because of its potential for radioimmunotherapy. Although 90Y has attractive properties for therapy, its secondary bremsstrahlung is less suitable for imaging and pharmacokinetic studies in patients. Thus, the pharmacokinetic data obtained for 111In-21T-BAD-Lym-1 in patients with NHL were used to calculate dosimetry for 90SY-21T-BAD-Lym-1. METHODS: Thirteen patients with advanced-stage NHLwere given a preload dose of unmodified Lym-1 followed by an imaging dose of 111In-21T-BAD-Lym-1. Sequential imaging and blood and urine samples obtained for up to 10 d after infusion were used to assess pharmacokinetics. Using 111In pharmacokinetic data and 90Y physical constants, radiation dosimetry for 90Y-21T-BAD-Lym-1 was determined. RESULTS: The uptake of 111In-21T-BAD-Lym-1 in tumors was greater than uptakes in the lung and kidney but similar to uptakes in the liver and spleen. The biologic half-time in tumors was greater than in lungs. The mean radiation dose to tumors was 6.57 +/- 3.18 Gy/GBq. The mean tumor-to-marrow (from blood) radiation ratio was 66:1, tumor-to-total body was 13:1, and tumor-to-liver was 1:1. Images of 111In were of excellent quality; tumors and normal organs were readily identified. Mild and transient Lym-1 toxicity occurred in 3 patients. CONCLUSION: Because of the long residence time of 111In-2IT-BAD-Lym-1 in tumors, high 90Y therapeutic ratios (tumor-to-tissue radiation dose) were achieved for some tissues, but the liver also showed high uptake and retention of the radiometal. (+info)
Imaging and phase I study of 111In- and 90Y-labeled anti-LewisY monoclonal antibody B3.
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B3 is a murine monoclonal antibody (mAb) that recognizes a LewisY carbohydrate antigen present on the surface of many carcinomas. An imaging and Phase I trial was performed to study the ability of 111In-mAb B3 to image known metastasis and determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), kinetics, and biodistribution of 90Y-mAb B3. Patients (n = 26) with advanced epithelial tumors that express the LewisY antigen were entered. All patients received 5 mCi of 111In-mAb B3 for imaging. 90Y-mAb B3 doses were escalated from 5 to 25 mCi in 5-mCi increments. 111In-mAb B3 and 90Y-mAb B3 were coadministered over a 1-h infusion. Definite tumor imaging was observed in 20 of 26 patients. Sites imaged included lung, liver, bone, and soft tissues. The MTD of 90Y-mAb B3 was determined to be 20 mCi. The DLTs were neutropenia and thrombocytopenia. Tumor doses ranged from 7.7 to 65.1 rad/mCi. 111In- and 90Y-mAb B3 serum pharmacokinetics (n = 23) were found to be similar. The amount of B3 administered (5, 10, and 50 mg) did not alter the pharmacokinetics. Bone marrow biopsies (n = 23) showed 0.0038+/-0.0016% of injected dose/gram for 111In-mAb B3 compared to 0.0046+/-0.0017% of injected dose/gram for 90Y-mAb B3 (P = 0.009). When given to patients with carcinomas that express the LewisY antigen, 111In-mAb B3 demonstrated good tumor localization. The MTD of 90Y-mAb B3 is 20 mCi, with myelosuppression as the DLT. Higher doses of radioactivity need to be delivered to achieve an antitumor effect. Humanized mAb B3 is being developed for evaluation in radioimmunotherapy. A clinical trial to explore the use of higher doses of 90Y-mAb B3 with autologous stem cell support is planned. (+info)
DNA cleavage by 111In-labeled oligodeoxyribonucleotides.
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We studied the fine structure of DNA damage produced by the decay of 111In incorporated into duplex and triplex DNA strands to evaluate the usefulness of this radionuclide for sequence-specific DNA cleavage. METHODS: Oligodeoxyribonucleotides (ODNs) were prepared with 111In attached by diethylenetriaminepentaacetic acid (DTPA) at the 5' end or 3' end through a long chemical linker or to an internal nucleotide position through a short linker. Subsequent formation of DNA duplexes and triplexes was confirmed by gel electrophoresis. The 111In-induced breaks were assayed in denaturing polyacrylamide gel electrophoresis with a single-nucleotide resolution. RESULTS: 111In-labeled oligonucleotides of high specific activity (740-1554 TBq/mmol) were synthesized. The presence of the bulky 111In-DTPA group did not impede duplex or triplex formation. Localized DNA breaks were observed in all duplexes and triplexes formed. The majority of DNA breaks in duplex formations were located within +/- 10 nucleotides from the site of attachment of the 111In-bearing linker. The yield of DNA breaks per decay was 0.38 in a duplex with internally modified ODNs. This is nearly 2 times less than the yield of DNA breaks in the same duplex with 1251 attached through the same linker. The yield of DNA breaks in the pyrimidine and purine strands of DNA triplexes with 111In attached to the triplex-forming ODNs through the linkers of different length varied from 0.05 to 0.10. The distribution of DNA breaks was wider in comparison with the duplex experiment. The lower yields of breaks per 111In decay compared with 125I may be not only the result of lower deposited energy but also of the ionic repulsion of the negatively charged 111In-DTPA group from the DNA strands. CONCLUSION: We have shown that decay of 111In produces highly localized DNA breaks. 111In introduced into triplex- and duplex-forming ODNs through hydrocarbon linkers produces sequence-specific DNA strand breaks with an efficiency nearly comparable with that of 1251. These findings are supportive of our proposed use of 111In-ODNs for gene-specific radiotherapy. (+info)
99mTc-HYNIC-[Tyr3]-octreotide for imaging somatostatin-receptor-positive tumors: preclinical evaluation and comparison with 111In-octreotide.
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In this paper we describe the preclinical evaluation of 99mTc-hydrazinonicotinyl-Tyr3-octreotide (HYNIC-TOC) using different coligands for radiolabeling and a comparison of their in vitro and in vivo properties with 111In-diethylenetriaminepentaacetic acid (DTPA)-octreotide. METHODS: HYNIC-TOC was radiolabeled at high specific activities using tricine, ethylenediaminediacetic acid (EDDA), and tricine-nicotinic acid as coligand systems. Receptor binding was tested using AR42J rat pancreatic tumor cell membranes. Internalization and protein binding studies were performed, and biodistribution and tumor uptake were determined in AR42J tumor-bearing nude mice. RESULTS: All 99mTc-labeled HYNIC peptides showed retained somatostatin-receptor binding affinities (Kd < 2.65 nM). Protein binding and internalization rates were dependent on the coligand used. Specific tumor uptake between 5.8 and 9.6 percentage injected dose per gram (%ID/g) was found for the 99mTc-labeled peptides, compared with 4.3 %ID/g for 111In-DTPA-octreotide. Tricine as coligand showed higher activity levels in muscle, blood, and liver, whereas tricine-nicotinic acid produced significant levels of activity in the gastrointestinal tract. EDDA showed the most promising overall biodistribution profile, with tumor-to-liver and tumor-to-gastrointestinal tract ratios similar to those obtained with 111In-DTPA-octreotide, lower ratios in blood and muscle, but considerably higher tumor-to-kidney ratios. CONCLUSION: TOC can be radiolabeled to high specific activities using HYNIC as a bifunctional chelator. The high specific tumor uptake, rapid blood clearance, and predominantly renal excretion make 99mTc-EDDA-HYNIC-TOC a promising candidate for an alternative to 111In-DTPA-octreotide for tumor imaging. (+info)
Biodistribution and pharmacokinetics of 111In-DTPA-labelled pegylated liposomes in a human tumour xenograft model: implications for novel targeting strategies.
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The biodistribution and pharmacokinetics of 111In-DTPA-labelled pegylated liposomes in tumour-bearing nude mice was studied to examine possible applications of pegylated liposome-targeted anti-cancer therapies. Nude mice received an intravenous injection of 100 microl of 111In-DTPA-labelled pegylated liposomes, containing 0.37-0.74 MBq of activity. The t1/2alpha and t1/2beta of 111In-DTPA-labelled pegylated liposomes were 1.1 and 10.3 h, respectively. Tumour uptake was maximal at 24 h at 5.5 +/- 3.0% ID g(-1). Significant reticuloendothelial system uptake was demonstrated with 19.3 +/- 2.8 and 18.8 +/- 4.2% ID g(-1) at 24 h in the liver and spleen, respectively. Other sites of appreciable deposition were the kidney, skin, female reproductive tract and to a lesser extent the gastrointestinal tract. There was no indication of cumulative deposition of pegylated liposomes in the lung, central nervous system, musculoskeletal system, heart or adrenal glands. In contrast, the t1/2alpha and t1/2beta of unencapsulated 111In-DTPA were 5 min and 1.1 h, respectively, with no evidence of accumulation in tumour or normal tissues. Incubation of 111In-DTPA-labelled pegylated liposomes in human serum for up to 10 days confirmed that they are very stable, with only minor leakage of their contents. The potential applications of pegylated liposomes in the arena of targeted therapy of solid cancers are discussed. (+info)
Recombinant versus natural human 111In-beta2-microglobulin for scintigraphic detection of Abeta2m amyloid in dialysis patients.
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BACKGROUND: We previously introduced scintigraphy with 131I-labeled beta2-microglobulin (beta2m), purified from uremic hemofiltrate, that is, "natural" beta2m, to specifically detect beta2m-associated amyloidosis (Abeta2m) in hemodialysis (HD) patients. METHODS: To improve the safety and resolution of the scan, we covalently bound the chelator diethylenetriaminepentaacetic acid to natural beta2m to allow radiolabeling with 111In. In a second step, we generated and evaluated the usage of recombinant human beta2m (rhbeta2m) for scintigraphy. RESULTS: Using natural 111In-labeled beta2m, eight patients on HD for 0 to 17 years, without evidence of Abeta2m, were scanned. Whole-body scintigraphy at 48 to 72 hours postinjection revealed no significant tracer accumulation over joint regions. In contrast, nine patients on HD for 10 to 21 years with clinical, radiological, or histologic (N = 4) evidence of Abeta2m showed selective tracer uptake over various joint regions. Tracer accumulation in visceral organs, which could not be related to tracer elimination or metabolism, was not detected. Compared with the previous 131I beta2m scan, scintigraphy with 111In-labeled beta2m offered highly improved image contrast, increased sensitivity, and a 50 to 70% reduction of the radiation exposure. Scanning with 111In-labeled recombinant human beta2m was performed in six patients: No significant tracer accumulation was observed over joint regions in two patients on short-term HD without evidence of Abeta2m; in contrast, local tracer accumulations similar to those observed with natural beta2m could be demonstrated in four long-term (10 to 27 years) HD patients with clinical, radiological, and histologic (N = 1) evidence of Abeta2m. CONCLUSION: Scintigraphy for Abeta2m with 111In-labeled rhbeta2m provides a homogenous and safe recombinant protein source and leads to enhanced sensitivity and lower radiation exposure. (+info)
Influence of tumour size on uptake of(111)ln-DTPA-labelled pegylated liposomes in a human tumour xenograft model.
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The relationship between tumour size and uptake of(111)In-DTPA-labelled pegylated liposomes has been examined in a human head and neck cancer xenograft model in nude mice. The mean tumour uptake of(111)In-labelled pegylated liposomes at 24 hours was 7.2 +/- 6.6% ID/g. Liposome uptake for tumours < 0.1 g, 0.1-1.0 g and > 1.0 g was 15.1 +/- 10.8, 5.9 +/- 2.2 and 3.0 +/- 1.3% ID/g, respectively. An inverse correlation between tumour weight and liposome uptake was observed by both Spearman's rank correlation test (r(s)= - 0.573, P< 0.001) and Pearson's correlation coefficient (r(s)= - 0.555, P< 0.001). For 18 tumours with macroscopic central necrosis, the ratio of uptake in the tumour rim relative to the necrotic tumour core was 11.2 +/- 6.4. Measurement of tumour vascular volume for tumours of various sizes revealed an inverse correlation between tumour weight and tumour vascular volume (Spearman's rank correlation test, r(s)= - 0.598, P< 0.001), consistent with poor or heterogeneous vascularization of larger tumours. These data have important implications for the clinical application of pegylated liposome targeted strategies for solid cancers which are discussed in detail. (+info)
High-dose therapy with 90Yttrium-labeled monoclonal antibody CC49: a phase I trial.
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A Phase I trial of increasing administered activities of 90yttrium (90Y)-labeled monoclonal antibody (MAb) CC49 was conducted to determine whether extrahematopoietic toxicity occurred with this radioimmunoconjugate. Twelve patients with various gastrointestinal tract cancers were administered a tracer dose of 111In-labeled MAb CC49 for biodistribution and pharmacokinetic studies. Patients then underwent a single treatment with increasing administered activities of 90Y-labeled MAb CC49 (0.3, 0.4, and 0.5 mCi/kg). Biodistribution studies, using 111In-labeled MAb CC49 as a surrogate, were determined using planar and single photon emission computed tomography imaging. Pharmacokinetic studies were performed by measuring radioactivity in blood samples taken at intervals after radioimmunoconjugate infusions. Tissue biopsies of tumor metastases and related normal tissues (liver and bone marrow) were obtained for radioactivity measurements. Radiation dosimetry estimates were calculated using these data. Toxicity was evaluated using the National Cancer Institute Common Toxicity Criteria. No dose limiting extrahematopoietic toxicity was identified in the range of administered activities used in this study. Radioimmunolocalization based on planar and single photon emission computed tomography images 111In-labeled MAb CC49 showed heterogeneous (nonspecific) liver and splenic uptake. Liver metastases were usually photopenic, and extrahepatic metastases showed faint to moderate uptake. The alpha and beta half-lives of 111In-labeled MAb CC49 and 90Y-labeled MAb CC49 in the blood were similar. Absorbed radiation dose estimates in metastatic tumor sites ranged from 180 to 3000 cGy. The percentage of injected dose/kg of tumor ranged from 1.12 to 18.14; however, tumor:normal liver ratios were consistently <1. No objective responses were observed. Doses of up to 0.5 mCi/kg could be administered with reversible grade IV myelotoxicity. Absorbed radiation dose in tumor was suboptimal, even at the highest administered activity level. Deposition of 90Y in liver was high, and estimates of absorbed dose in liver equaled or exceeded that which could be achieved in metastatic tumor sites. Strategies to enhance access of radioimmunoconjugates in tumor and diminish deposition in the liver need to be developed for effective treatment using MAb CC49 with chelated radiometals. (+info)