| Abstract: |
Purpose: The aim of the study was to establish and refine a preclinical model to α-immunoradiotherapy of ovarian cancer. Experimental Design: At-211 was produced by cyclotron irradiation of a bismuth-209 target and isolated using a novel dry distillation procedure. Monoclonal antibodies were radiohalogenated with the intermediate reagent N-succinimidyl 3-(trimethylstannyl)benzoate and characterized in terms of radiochemical yield and in vitro binding properties. In vitro OVCAR-3 cells were irradiated using an external Cobalt-60 beam, as reference, or At-211-albumin and labeled antibody. Growth assays were used to establish cell survival. A Monte Carlo program was developed to simulate the energy imparted and the track length distribution. Nude mice were used for studies of WBC depression, with various activities of Tc-99m antibodies, as reference, and At-211 antibodies. In efficacy studies, OVCAR-3 cells were inoculated i.p., and animals were treated 2 weeks later. The animals were either dissected 6 weeks later or followed-up for long-term survival. Results: A rapid distillation procedure, as well as a rapid and high-yield, single-pot labeling procedure, was achieved. From growth inhibition data, the relative biological effectiveness of the α-emission for OVCAR-3 cells was estimated to be approximately 5, which is in the same range as found in vivo for hematological toxicity. At-211 MOv18 was found to effectively inhibit the development of tumors and ascites, also resulting in long-term survival without significant toxic effect. Conclusions: Use of the short-range, high-linear energy transfer α-emitter At-211 conjugated to a surface epitoperecognizing monoclonal antibody appears to be highly efficient without significant toxicity in a mouse peritoneal tumor model, urging a Phase I clinical trial. |
| Keywords: |
cancer survival; controlled study; treatment outcome; unclassified drug; human cell; drug activity; cancer growth; drug efficacy; nonhuman; conference paper; cancer radiotherapy; ovarian neoplasms; isotopes; mouse; animals; mice; animal tissue; cell survival; cell division; cancer immunotherapy; ovary cancer; cell growth; blood toxicity; leukopenia; animal experiment; animal model; cancer cell culture; in vitro study; cell line, tumor; mice, inbred balb c; time factors; dose-response relationship, radiation; monoclonal antibody; antibodies, monoclonal; isotope labeling; nude mouse; tissue distribution; mice, nude; radiometry; leukocyte count; neoplasm transplantation; radiation beam; radioimmunotherapy; cobalt 60; drug binding; cyclotron; clinical trials; monte carlo method; growth inhibition; astatine 211; distillation; astatine; humans; human; female; priority journal; monoclonal antibody at 211; monoclonal antibody tc 99m; murine monoclonal antibody mov18 at 211; benzoates; trimethyltin compounds
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