astatine and Brain-Neoplasms

Topics: Alpha Particles; Animals; Antibodies, Monoclonal; Astatine; Benzoates; Brain Neoplasms; Cell Line, Tumor; Glioma; Humans; Isotope Labeling; Mice; Radioimmunotherapy; Tissue Distribution; Trimethyltin Compounds; Xenograft Model Antitumor Assays

Increased amino acid transport in brain tumours is used for diagnostic purposes. It has been shown that the α-emitting radionuclide astatine-211 labeled to L-phenylalanine is taken up by glioblastoma cells. We here tested, if systemic treatment with 4-[211At]astatine-phenylalanine (At-Phe) has a beneficial effect on survival of rats with intracranial glioblastoma.. The rat glioblastoma cell line BT4Ca was implanted into the prefrontal cortex of female BDIX rats by stereotaxic microinjection (10,000 cells/3 µl; n = 83). 3 days after implantation At-Phe or phosphate buffered saline were injected intravenously. A third group was treated twice, i.e., on day 3 and 10. Health condition was assessed each day by using a score system. Rats were sacrificed on days 6, 10, 13 and 17 after implantation, or when showing premortal health condition to measure tumour volume and necrosis. The proliferation index (PI) was assessed after immunohistochemical staining of Ki-67.. Survival time of rats treated twice with At-Phe was significantly prolonged. Additionally, both At-Phe-treated groups remained significantly longer in a better health condition. Rats with poor health status had larger tumours than rats with fair health condition. Overall, irrespective of treatment the PI was reduced in rats with poor health condition. Necrosis was larger in rats treated twice with At-Phe.. Intravenous treatment with At-Phe enhanced survival time of rats with intracranial glioblastomas and improved health condition. These results encourage studies using local treatment of intracranial glioblastoma with At-Phe, either by repeated local injection or by intracavital application after tumour resection.

Topics: Animals; Astatine; Brachytherapy; Brain Neoplasms; Cell Line, Tumor; Dose-Response Relationship, Radiation; Female; Glioblastoma; Phenylalanine; Radiopharmaceuticals; Rats; Survival Rate; Treatment Outcome

2-[211At]-L-phenylalanine and 4-[211At]-L-phenylalanine were prepared from the corresponding iodo and bromo derivatives using the Cu(+)-assisted nucleophilic exchange. 4-[211At]-L-phenylalanine was additionally prepared by destannylation of the BOC-derivatized 4-tributylstannyl-L-phenylalanine. Radiochemical yields of 2-[211At]-L-phenylalanine and 4-[211At]-L-phenylalanine by nucleophilic exchange were 52-74% and 65-85%. Radiochemical yield of 4-[211At]-L-phenylalanine by electrophilic destannylation was 35-50%. HPLC sequence analysis showed that 2-[211At]-L-phenylalanine followed the halogen sequence (F

Topics: Astatine; Brain Neoplasms; Cell Line, Tumor; Glioma; Humans; Isotope Labeling; Phenylalanine; Radiopharmaceuticals

Topics: Alpha Particles; Animals; Antineoplastic Agents; Astatine; Bismuth; Brain Neoplasms; Cell Line, Tumor; Female; Humans; Mice; Ovarian Neoplasms; Radioimmunotherapy; Radioisotopes

alpha-Particle-emitting radionuclides, such as (211)At, with a 7.2-h half-life, may be optimally suited for the molecularly targeted radiotherapy of strategically sensitive tumor sites, such as those in the central nervous system. Because of the much shorter range and more potent cytotoxicity of alpha-particles than of beta-particles, (211)At-labeled agents may be ideal for the eradication of tumor cells remaining after surgical debulking of malignant brain tumors. The main goal of this study was to investigate the feasibility and safety of this approach in patients with recurrent malignant brain tumors.. Chimeric antitenascin monoclonal antibody 81C6 (ch81C6) (10 mg) was labeled with 71-347 MBq of (211)At by use of N-succinimidyl 3-[(211)At]astatobenzoate. Eighteen patients were treated with (211)At-labeled ch81C6 ((211)At-ch81C6) administered into a surgically created resection cavity (SCRC) and then with salvage chemotherapy. Serial gamma-camera imaging and blood sampling over 24 h were performed.. A total of 96.7% +/- 3.6% (mean +/- SD) of (211)At decays occurred in the SCRC, and the mean blood-pool percentage injected dose was < or = 0.3. No patient experienced dose-limiting toxicity, and the maximum tolerated dose was not identified. Six patients experienced grade 2 neurotoxicity within 6 wk of (211)At-ch81C6 administration; this neurotoxicity resolved fully in all but 1 patient. No toxicities of grade 3 or higher were attributable to the treatment. No patient required repeat surgery for radionecrosis. The median survival times for all patients, those with glioblastoma multiforme, and those with anaplastic astrocytoma or oligodendroglioma were 54, 52, and 116 wk, respectively.. This study provides proof of concept for regional targeted radiotherapy with (211)At-labeled molecules in oncology. Specifically, the regional administration of (211)At-ch81C6 is feasible, safe, and associated with a promising antitumor benefit in patients with malignant central nervous system tumors.

Topics: Adult; Aged; Alpha Particles; Antibodies, Monoclonal; Astatine; Astrocytoma; Brain Neoplasms; Feasibility Studies; Female; Glioblastoma; Humans; Isotope Labeling; Male; Middle Aged; Neoplasm Recurrence, Local; Oligodendroglioma; Radioimmunotherapy; Radioisotopes; Radiopharmaceuticals; Survival Rate; Tenascin

To establish the theoretical framework and study the feasibility of (211)At-labeled anti-tenascin chimeric 81C6 monoclonal antibody (mAb) as anti-vascular endoradiotherapy for the treatment of glioblastoma multiforme (GBM) tumors.. The morphology of blood vessels from histologic images was analyzed and used along with reaction-diffusion equations to assess the activity concentration of (211)At-labeled chimeric 81C6 mAb in GBM tumor and normal-brain tissue. Alpha particle microdosimetry was then used to assess the survival probability and average absorbed dose for tumor and normal tissue endothelial cells (ECs) per unit vascular cumulated activity concentration q(source) (MBq-s g(-1)). In turn, these survival probabilities were used to assess the probability of failure Phi for a single vessel. Furthermore, using the vessel density, the specific tumor control probability per unit mass of tumor tissue (tcp) and the specific normal-tissue complication probability per unit mass of normal-brain tissue (ntcp) were estimated. The specific tumor control probability, tcp, was used to assess the overall tumor control probability (TCP) as a function of tumor mass.. The levels of (211)At-labeled ch81C6 mAb cumulated activity concentration in GBM tumor tissue were approximately five times higher than that in normal-brain tissue. Thus, the average absorbed dose to tumor ECs was higher than that of normal tissue ECs, and the survival probability for GBM ECs was lower than for normal-brain tissue ECs. Consequently, the resulting vessel-failure probability, Phi, for GBM tumor and for normal-brain tissue differ considerably, yielding a q(source) range between 10(3) and 10(4) MBq-s g(-1).. This theoretical analysis demonstrated that (211)At-labeled chimeric 81C6 is an effective anti-vascular therapy for the treatment of GBM tumors, yielding a tcp higher than 0.999 for vascular cumulated activity concentrations q(source) higher than 1 x 10(4) MBq-s g(-1), while yielding a low probability for normal-brain tissue damage.

Topics: Alpha Particles; Astatine; Boron Neutron Capture Therapy; Brain; Brain Neoplasms; Glioblastoma; Humans; Probability; Radioimmunotherapy; Radiometry; Tenascin

It was intended to test the biological response (poly-ADP-ribosylation of cellular proteins) of alpha-particles from extracellular 211At for enhanced damage to human glioblastoma cells in vitro and to discuss its suitability for potential application in therapy of high-grade gliomas.. Confluent cultures of human glioblastoma cells were exposed to different doses of alpha-radiations from homogeneously distributed extracellular 211At. Cellular poly-ADP-ribosylation of all proteins including histones was monitored since it is an indirect but sensitive indicator of chromatin damage and putative repair in both normal and malignant mammalian cells.. A significant diminution (average 85.6%) in poly-ADP-ribosylation of total cellular proteins relative to that for non-irradiated glioblastoma cells was observed following 0.025 to 1.0 Gy alpha-radiations. In the dose range of 0.0025 to 0.01 Gy there was an increase with a maximum value of approximately 119.0% at 0.0025 Gy. Below 0.0025 Gy no change in poly-ADP-ribosylation was observed.. Level of cellular poly-ADP-ribosylation of proteins at 0.025 to 1.0 Gy of alpha-radiation dose from 211At appears to cause enhanced damage by creating molecular conditions which are not conducive to repair of DNA damages in human glioblastoma cells in vitro. Therefore, it is assumed that clinical application of 211At at least in this dose range might enhance clinical efficacy in radiotherapy of cancer.

Topics: Alpha Particles; Astatine; Brain Neoplasms; Chromosomal Proteins, Non-Histone; DNA Repair; Dose-Response Relationship, Radiation; Glioblastoma; Humans; In Vitro Techniques; Linear Energy Transfer; Poly Adenosine Diphosphate Ribose; Protein Processing, Post-Translational; Tumor Cells, Cultured