Therapeutic efficacy of astatine-211-labeled trastuzumab on radioresistant SKOV-3 tumors in nude mice

Purpose: To investigate the potential use of astatine-211 (At-211)-labeled trastuzumab for the treatment of HER2-positive, radioresistant ovarian carcinoma. Methods and Materials: Four-week-old nude mice were inoculated intraperitoneally with 5.10(6) SKOV-3 cells in 0.4 mL saline on Day 0. The endpoint was the total tumor weight in each mouse on Day 63. Three experiments were performed in which the response to single-dose and fractionated treatment with unlabeled and 21 At-labeled antibody was evaluated. Results: Experiment 1 showed, for the same total amount of trastuzumab, a dose-response relationship between At-211 activity (0-400 kBq on Day 7) and therapeutic efficacy (p = 0.001). The effect of varying the amount of unlabeled trastuzumab was studied in Experiment 2. All mice, except for the controls, received 400 kBq At-211-trastuzumab, and different groups received 5, 50, or 500 mu g trastuzumab on Day 7. The increase from 5 to 50 jig trastuzumab reduced the tumors by 78% in weight. No tumors were present in mice given 500 mu g trastuzumab. In Experiment 3, the effect of a fractionated treatment regimen was studied. Mice that received 100 kBq At-211-trastuzumab on Days 7 and 8 had a 42% smaller tumor burden than did controls. Groups of mice injected with 200 + 100 kBq on Days 7 and 21 and mice injected with 100 kBq on Days 7, 8, and 21 both had 24 % less tumor weight than the corresponding controls. Conclusion: The combination of 500 mu g trastuzumab and 400 kBq At-211-trastuzumab had the greatest effect, with complete eradication of the tumors in this nude mouse model. (c) 2007 Elsevier Inc.