Mutagenicity tests of 4-phenyl-1,3-dithia-2-thioxo-cyclopent-4-ene.
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The mutagenicity of 4-phenyl-1,3-dithia-2-thioxo-cyclopent-4-ene (DT827B) was examined in reverse mutation tests using Salmonella typhimurium and Escherichia coli, in the chromosomal aberration test with Chinese hamster ovary (CHO) cells, and in the micronucleus test using mice bone-marrow. In reverse mutation assay on DT827B according to Ames' method, DT827B was not mutagenic to S. typhimurium or E. coli when tested in dimethylsulfoxide to the limit of its solubility where precipitation occurred. In chromosomal aberration assay using CHO cells, DT827B was not clastogenic to induce structural chromosomal aberration but capable of inducing polyploidy. In micronucleus test, DT827B did not show micronucleus-inducing potential at the maximum dose. In conclusion of the three mutagenicity studies, DT827B was considered to cause no mutagenicity under the conditions used in the present experiments except the increase in polyploidy, which probably is due to a toxic effect of the compound. (+info)
Cure of human carcinoma xenografts by a single dose of pretargeted yttrium-90 with negligible toxicity.
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A covalent conjugate (NR-LU-10/SA) was prepared between streptavidin (SA) and NR-LU-10, a mAb that binds an antigen expressed on the surface of most human carcinomas. NR-LU-10/SA was injected into nude mice bearing human tumor xenografts. Injection of biotinylated galactosyl-human serum albumin reduced the circulating levels of conjugate by 95%. Subsequent administration of (90)Y-1,4,7, 10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-biotin achieved peak uptake at the tumor within 2 hr while >80% of the radioactivity was eliminated in the urine. A single dose of 600-800 microCi of (90)Y-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-biotin produced cures in 10/10 mice with established (>200 mm(3)) s.c. human small cell lung or colon cancer xenografts and 8/10 cures in mice with human breast cancer xenografts without significant toxicity. (+info)
Disposition in rats of N-pyridinium-propyl-cyclam, N-triethylammonium-propyl-cyclam, and N-[Triethylammonium]-3-propyl-[15]ane-N5, potential cartilage imaging agents.
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Quaternary ammonium compounds are known to highly concentrate in articular cartilages after i.v. administration. This property was used to synthesize new potential radiodiagnostic agents for joint imaging. Pharmacokinetic study was performed in rats for three new compounds: N-pyridinium-propyl-cyclam (NPPC), N-triethylammonium-propyl-cyclam (NTPC), and N-[triethylammonium]-3-propyl-[15]ane-N5 (NTP 15-5). After i.v. administration, [(3)H]NPPC and [(3)H]NTPC highly and rapidly concentrated in articular cartilage, this uptake being followed by a single exponential decrease with half-lives of, respectively, 75 and 82 min. Except cartilage, only the kidney was highly labeled. After complexation of (99m)Tc by NPPC, NTPC, and NTP 15-5, only (99m)Tc-NTP 15-5 exhibited a high affinity for cartilage. On the other hand, the pharmacokinetic behavior of (99m)Tc-NTPC and (99m)Tc-NPPC was very different from those of their (3)H-labeled analogs. Concentration in cartilaginous tissues was strongly diminished, and liver and bone were highly labeled. For all labeled species, the major route of excretion was urine, and HPLC analysis showed that [(3)H]NTPC and [(3)H]NPPC were excreted under their unchanged form. On the other hand, no (99m)Tc-NTPC and (99m)Tc-NPPC were found in the urine, the radioactivity being mainly due to free technetium, contrary to (99m)Tc-NTP 15-5, which was excreted in the urine under the complexed form. These data can explain the striking differences observed between the three (99m)Tc-labeled molecules, the lack of concentration of (99m)Tc-NTPC, and (99m)Tc-NPPC in cartilages in comparison with their (3)H-labeled analogs due to an instability in vivo of these technetiated complexes. (+info)
Joint scintigraphy in rabbits with 99mtc-N-[3-(triethylammonio)propyl]-15ane-N5, a new radiodiagnostic agent for articular cartilage imaging.
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The aim of this study was to investigate joint scintigraphy in rabbits with 99mTc-N-[3-(triethylammonio)propyl]-15ane-N5 (NTP 15-5), a new radiopharmaceutical that specifically localizes in cartilaginous tissues. METHODS: Scans obtained after intravenous injection of the 99mTc-labeled compound in normal and arthropathy-induced rabbits were compared with those of the bone-imaging agent 99mTc-methylene diphosphonate (99mTc-MDP). RESULTS: The radioactive uptake of 99mTc-NTP 15-5 was detected in cartilaginous tissues 5 min after injection and was stable for 2 h. The uptake intensity was related to age and joint disease severity, and cartilage alterations not revealed by radiography induced a significant decrease of radiotracer uptake. On the other hand, imaging performed with 99mTc-MDP did not reveal the early changes in arthrosis but was more specific for bone remodeling in advanced stages of diseases or in inflammatory processes. CONCLUSION: Our results indicate that 99mTc-NTP 15-5 could be a good tracer for human arthrosic and arthritic cartilage detection, especially for the early diagnosis of joint diseases. (+info)
X-ray absorption studies of human matrix metalloproteinase-2 (MMP-2) bound to a highly selective mechanism-based inhibitor. comparison with the latent and active forms of the enzyme.
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Malignant tumors express high levels of zinc-dependent endopeptidases called matrix metalloproteinases (MMPs), which are thought to facilitate tumor metastasis and angiogenesis by hydrolyzing components of the extracellular matrix. Of these enzymes, gelatinases A (MMP-2) and B (MMP-9), have especially been implicated in malignant processes, and thus, they have been a target for drugs designed to block their activity. Therefore, understanding their molecular structure is key for a rational approach to inhibitor design. Here, we have conducted x-ray absorption spectroscopy of the full-length human MMP-2 in its latent, active, and inhibited states and report the structural changes at the zinc ion site upon enzyme activation and inhibition. We have also examined the molecular structure of MMP-2 in complex with SB-3CT, a recently reported novel mechanism-based synthetic inhibitor that was designed to be highly selective in gelatinases. It is shown that SB-3CT directly binds the catalytic zinc ion of MMP-2. Interestingly, the novel mode of binding of the inhibitor to the catalytic zinc reconstructs the conformational environment around the active site metal ion back to that of the proenzyme. (+info)
111In-labeled 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid-lys(8)-vasotocin: a new powerful radioligand for oxytocin receptor-expressing tumors.
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We developed a radioactive ligand for tumors expressing oxytocin receptors (OTRs) by linking the chelating agent 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid (DOTA) to Lys(8)-vasotocin (LVT), an analogue of oxytocin with high affinity for OTRs. The new reagent (DOTA-LVT) retained high affinity for human OTRs, as proved by in vitro affinity binding to cells endogenously expressing OTRs, such as MCF7 breast carcinoma and MOG-U-V-W glioblastoma cells lines, as well as to transiently transfected COS7 cells. In in vivo experiments, DOTA-LVT carrying (111)In showed specific binding activity to OTR-positive TS/A mouse mammary tumors. The present study opens new perspectives for imaging and, possibly, therapy of OTR-positive human tumors such as breast and endometrial carcinomas, neuroblastomas, and glioblastomas. (+info)
Radioimmunotherapy of a human lung cancer xenograft with monoclonal antibody RS7: evaluation of (177)Lu and comparison of its efficacy with that of (90)Y and residualizing (131)I.
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Tumor targeting and therapeutic efficacy of (177)Lu-labeled monoclonal antibody (mAb) RS7 (antiepithelial glycoprotein-1) was evaluated in a human nonsmall cell lung carcinoma xenograft model. The potential of (177)Lu-labeled RS7 was compared with that of RS7 labeled with (90)Y and a residualizing form of (131)I. METHODS: A 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid (DOTA) conjugate of RS7 was used for radiolabeling with (177)Lu-acetate or (88/90)Y-acetate. Biodistribution and therapy studies were conducted in nude mice with subcutaneous Calu-3 xenografts. Therapy studies were performed using the maximal tolerated doses (MTDs) of (90)Y-DOTA-RS7 (3.9 MBq [105 microCi]) and (177)Lu-DOTA-RS7 (10.2 MBq [275 microCi]) and compared with the data obtained using the MTD (13.0 MBq [350 microCi]) of a residualizing form of (131)I-RS7. RESULTS: Radiolabeling of RS7-DOTA conjugate with (177)Lu-acetate was facile. (177)Lu-DOTA-RS7 displayed biodistribution results that were nearly identical to that of the (88)Y analog in a paired-label study. The mean percentage injected doses per gram (%ID/g) for (177)Lu-RS7 and (88)Y-RS7 (in parentheses) in tumor were 38.3 %ID/g (39.1 %ID/g), 63.0 %ID/g (66.0 %ID/g), 63.0 %ID/g (65.8 %ID/g), and 34.0 %ID/g (34.9 %ID/g) on days 1, 3, 7, and 14, respectively. Elimination of established tumors, with an initial mean tumor volume of 0.24 cm(3), was shown using doses of (177)Lu-DOTA-RS7 ranging from 5.6 to 9.3 MBq (150--250 microCi) per nude mouse, with no significant difference in response rate noted between the doses in this range. Specificity of the therapeutic effect was shown in an isotype-matched control experiment, in which (177)Lu-DOTA-RS7 was markedly more effective than the (177)Lu-DOTA control antibody. A comparison of the therapeutic efficacies of (177)Lu-DOTA-RS7 and (90)Y-DOTA-RS7, using mice with established tumors with an initial mean tumor volume of 0.85 cm(3), indicated similar tumor growth inhibition and similar tumor regrowth profiles. The therapy data were similar to those obtained with residualizing (131)I-RS7 obtained at the same time. CONCLUSION: (177)Lu-RS7 is an effective radioimmunoconjugate for radioimmunotherapy. With its radiophysical properties similar to those of (131)I, coupled with its facile and stable attachment to mAb, (177)Lu promises to be an alternative to (131)I, and a complement to (90)Y, in radioimmunotherapy. (+info)
111In-DOTA-lanreotide scintigraphy in patients with tumors of the lung.
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Imaging with radiolabeled somatostatin (SST) analogs has recently been established for the localization of various human SST receptor (hsstr)-positive tumors, including neuroendocrine tumors, lymphomas, and non-small cell lung cancer (NSCLC). METHODS: 111In-1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid-lanreotide (DOTA-LAN) scintigraphy (150 MBq; 7 nmol per patient) was performed on 47 patients (28 patients with primary tumors, 19 patients with lung metastases from other tumors) to evaluate the tumor binding in patients with histologically confirmed lung cancer. A group of 27 tumor patients without documented lung lesions served as the control group. Early and delayed planar and SPECT images were acquired. Whole-body scintigraphy was performed at 0.5, 4-6, 24, and 48 h after injection for tumor dose estimation. In addition, hsstr subtype expression and radioligand binding characteristics were studied in vitro using lung tumor samples (n = 15). RESULTS: 111In-DOTA-LAN indicated the primary lung tumor in 16 of 16 NSCLC patients. Lymph node metastases were visualized in 6 of 6 NSCLC patients, and bone metastases were seen in 3 of 3 NSCLC patients. 111In-DOTA-LAN scintigraphy indicated lung carcinoid in 5 of 5 patients and small cell lung cancer lesions in 6 of 6 patients. Multiple lung metastases were shown in all 6 patients with non-Hodgkin's lymphoma and in the 1 patient with Hodgkin's disease, 5 of 5 colorectal adenocarcinoma patients, 4 of 4 carcinoid patients, 2 of 2 neuroendocrine carcinoma (NEC) patients, and 1 of 1 angiosarcoma patient. Pulmonary tumor sites not indicated by CT or MRI were visualized in 6 of 47 tumor patients (i.e., 13%; lung metastases in 1 carcinoid patient and 1 NEC patient, lymph node metastases in 1 carcinoid patient and 2 NSCLC patients, bone metastases in 1 carcinoid patient). The estimated lung tumor dose ranged between 0.2 and 5 mGy/MBq. Focal lung uptake of 111In-DOTA-LAN was not observed in any of the 27 control patients. In vitro binding studies indicated high-affinity binding sites for 111In-DOTA-LAN in NSCLC samples (dissociation constants, 0.5 and 4 nmol/L) with predominant expression of hsstr4. CONCLUSION: 111In-DOTA-LAN yields high tumor binding for various human lung tumors. Consecutively, radiopeptide therapy may offer a potential new treatment alternative for some lung tumor patients. (+info)