1.
Andersson, Håkan, 1944, et al.
(författare)
Astatine-211-labeled antibodies for treatment of disseminated ovarian cancer: an overview of results in an ovarian tumor model
2003
Ingår i: Clin Cancer Res. - 1078-0432. ; 9:10 Pt 2
Tidskriftsartikel (refereegranskat) abstract
PURPOSE: The aim of the study was to establish and refine a preclinical model to alpha-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 alpha-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 alpha-emitter At-211 conjugated to a surface epitope-recognizing monoclonal antibody appears to be highly efficient without significant toxicity in a mouse peritoneal tumor model, urging a Phase I clinical trial.
2.
Elmroth, Kerstin, 1970, et al.
(författare)
Chromatin- and temperature-dependent modulation of radiation-induced double-strand breaks
2003
Ingår i: International Journal of Radiation Biology. - : Informa UK Limited. - 0955-3002 .- 1362-3095. ; 79:10, s. 809-816
Tidskriftsartikel (refereegranskat) abstract
Purpose: To investigate the influence of chromatin organization and scavenging capacity in relation to irradiation temperature on the induction of double-strand breaks (DSB) in structures derived from human diploid fibroblasts. Materials and methods: Agarose plugs with different chromatin structures (intact cells±wortmannin, permeabilized cells with condensed chromatin, nucleoids and DNA) were prepared and irradiated with X-rays at 2 or 37°C and lysed using two different lysis protocols (new ice-cold lysis or standard lysis at 37°C). Induction of DSB was determined by constant-field gel electrophoresis. Results: The dose-modifying factor (DMFtemp) for irradiation at 37 compared with 2°C was 0.92 in intact cells (i.e. more DSB induced at 2°C), but gradually increased to 1.5 in permeabilized cells, 2.2 in nucleoids and 2.6 in naked DNA, suggesting a role of chromatin organization for temperature modulation of DNA damage. In addition, DMFtemp was influenced by the presence of 0.1 M DMSO or 30 mM glutathione, but not by post-irradiation temperature. Conclusion: The protective effect of low temperature was correlated to the indirect effects of ionizing radiation and was not dependent on post-irradiation temperature. Reasons for a dose modifying factor <1 in intact cells are discussed.
3.
Lindegren, Sture, 1960, et al.
(författare)
(211)At-labeled and biotinylated effector molecules for pretargeted radioimmunotherapy using poly-L- and poly-D-Lysine as multicarriers
2003
Ingår i: Clin Cancer Res. - 1078-0432. ; 9:10 Pt 2
Tidskriftsartikel (refereegranskat) abstract
Poly-L- and poly-D-lysine were evaluated as carriers of astatine and biotin for prospective use as effector molecules in pretargeted radioimmunotherapy of micrometastases. The precursor polylysine was derivatized in a three-step, single-pot procedure, including biotinylation with biotin amidocaproic N-hydroxysuccinimide, astatination via the intermediate reagent N-succinimidyl 3-(trimethylstannyl)benzoate, and, finally, charge modification using succinic anhydride. The chemistry was shown to be very facile, with a biotinylation efficiency of 75 +/- 5%, and overall radiochemical yields in the range of 50-70%. After charge modification, no amines could be detected in the final product. The biotin function was unaffected by the chemistry and the radiation, as confirmed by almost complete binding of the effector molecule to avidin beads using a convenient filter tube assay. The effector molecules were evaluated in tumor-free female nude mice with regard to whole-body retention and tissue distribution after i.p. administration. The distribution of the L-isomer effector molecule showed rapid whole-body clearance with low uptake in all tissues, whereas the D-isoform showed whole-body clearance related to uptake in the kidneys. Both D-isomer and L-isomer showed faster blood clearance and generally lower tissue uptakes than labeled antibodies. The normal tissue distribution after the peritoneal administration implies that pretargeting using L-structure polylysine as the effector molecule may give a higher therapeutic index than that achieved in conventional radioimmunotherapy.
4.
Palm, Stig, 1964, et al.
(författare)
Single-cell irradiation from [211At] astatine-labeled C215 monoclonal antibody: improved estimates of radiosensitivity from measurements on cellular uptake and retention
2003
Ingår i: Anticancer Res. - 0250-7005. ; 23:2B, s. 1219-21
Tidskriftsartikel (refereegranskat) abstract
New data on the biological effect of 211At-C215 monoclonal antibody in a slowly rotating, widely dispersed single-cell suspension of the human cancer cell line Colo-205 is presented. Cell growth curves of each experiment were used to calculate an apparent cell survival after irradiation. Uptake measurements provided the data needed to calculate the average number of 211At decays per cell in the cell suspension. The results from each experiment were then fit to a mono-exponential function. From the exponential fit, an average of 35 +/- 2 (SD) astatine-211 decays per cell are required for 37% apparent cell survival (D0).
