Fractionated radio immunotherapy of intraperitoneally growing ovarian cancer in nude mice with 211At-MX35 F(ab′)2:: therapeutic efficacy and myelotoxicity

Objective: The aim of this study was to investigate the therapeutic efficacy and myelotoxicity during fractionated radio immunotherapy of ovarian cancer in mice. The study was performed using the monoclonal antibody MX35 F(ab')(2) labeled with the a-particle emitter At-211. Methods: Animals were intraperitoneally inoculated with similar to 1 x 10(7) cells of the cell line NIH:OVCAR-3. Four weeks later, the mice were given the first treatment. Six groups of animals were intraperitoneally injected with similar to 800, 3 x similar to 267, similar to 400, 3 x similar to 133, similar to 50 or 3 x similar to 17 kBq At-211-MX35 F(ab')(2) (n = 18 in each group). The second and third injections for Groups 2, 4 and 6 were given 4 and 8 days after the first injection, respectively. As controls, animals were treated with unlabeled MX35 F(ab')(2) (n = 12). Eight weeks after the last injection, the animals were sacrificed and the presence of macro- and microscopic tumors and ascites was determined. Blood counts were determined for each mouse in Groups 1 and 2 before the first injection and 3, 7, 11, 15 and 23 days after the first injection. The calculation of the mean absorbed dose to the bone marrow was based on the ratio between the At-211-activity concentration in bone and blood [i.e., the bone-to-blood ratio (BBLR)] as well as that between the At-211-activity concentration in bone marrow and blood [i.e., the bone-marrow-to-blood ratio (BMBLR)] and the cumulated activity and absorbed fraction of the alpha-particles emitted by At-211 in the bone marrow. Results: The tumor-free fractions of animals were 56% and 41% when treated with similar to 800 kBq and 3 x similar to 267 kBq At-211-MX35 F(ab')(2), respectively; 39% and 28% when treated with similar to 400 kBq and 3 x similar to 133 kBq At-211-MX35 F(ab')(2), respectively; and 17% and 22% when treated with similar to 50 kBq or 3 x similar to 17 kBq At-211-MX35 F(ab')(2), respectively. The nadir of the white blood cell (WBC) counts was decreased (from 46% to 19%, compared with the baseline WBC counts) and delayed (from Day 4 to Day 11 after the first injection) during the fractionated treatment compared with the single-dose treatment. The percentage of injected activity per gram (%IA/g) for blood, bone and bone marrow all peaked 6 h after injection at 13.80 +/- 1.34% IA/g, 4.00 +/- 0.69%IA/g and 8.28 +/- 1.38%IA/g, respectively. The BBLR and BMBLR were 0.20 +/- 0.04 and 0.58 +/- 0.01, respectively. The mean absorbed dose to bone marrow was similar to 0.4 Gy after intraperitoneally injecting similar to 800 kBq At-211-MX35 F(ab')(2). Conclusion: No advantage was observed in the therapeutic efficacy of using a fractionated regimen compared with a single administration, with the same total amount of administered activity. Alleviation of the myelotoxicity was observed during the fractionated regimen in terms of decreased suppression and delayed nadir of the WBC counts. No thrombocytopenia was observed during either regimen. (c) 2006 Elsevier Inc. All rights reserved.