Presentation Effects of alpha-emitting meta-211At-astato-benzylguanidine (211At-MABG) on tumor growth suppression in a pheochromocytoma mouse model with histological analysis

Sudo, Hitomi  ,  Sugyo, Aya  ,  Tsuji, Atsushi  ,  Nagatsu, Kotaro  ,  Ohshima, Yasuhiro  ,  S.Ishioka, Noriko  ,  Higashi, Tatsuya  ,  Yoshinaga, Keiichiro

Objectives: Therapeutic options for patients with malignant pheochromocytoma are currently limited, and therefore new treatment approaches are being sought. Alpha-emitting radiopharmaceutical meta-211At-astatobenzylguanidine (211At-MABG) has potential as a malignant pheochromocytoma treatment. We previously reported the effects of using 30 µCi of 211At-MABG on tumor growth suppression in a pheochromocytoma mouse model. However, the histological impacts of 211At-MABG on tumor cells have not been evaluated. Therefore, the purpose of this study was to evaluate the histological changes associated with and therapeutic efficacy of various doses of 211At-MABG in the mouse pheochromocytoma model.Methods: Rat pheochromocytoma (PC-12) cells were subcutaneously inoculated into female nude mice. When tumor volumes reached approximately 50 mm3, mice bearing PC-12 tumors received 0 (saline), 15, 30, 50, 100 and 150 µCi of 211At-MABG (n = 5 each dose). The tumor volume and body weight were measured twice weekly for 8 weeks. Tumors and organs of interest were resected 8 weeks after 211At-MABG administration or when the mice were humanely euthanized in cases of excessive weight reduction. The tumor volume, tumor volume rate and body weight data were analyzed by ANOVA with the Student's t-test. For histological analysis of temporal change, tumors and organs of another group treated with 30 µCi of 211At-MABG were resected on days 1, 3 and 7. The histological sections of tumors and organs were stained with hematoxylin and eosin.Results: The control group injected with saline (0 µCi) had significantly increased tumor volume after 3 weeks (48.9 ± 7.7 mm3 to 296.1 ± 56.2 mm3, P < 0.01). In contrast, the 211At-MABG treatment group had significantly reduced tumor volumes 3 weeks after 211At-MABG administration (15 µCi: 48.9 ± 7.8 mm3 to 4.5 ± 2.3 mm3, P <0.01, and 30 µCi: 48.7 ± 8.0 mm3 to 1.7 ± 1.9 mm3, P < 0.01). Baseline tumor volume was similar in the control and 211At-MABG treatment groups. There were significant differences in tumor volumes between the control and 211At-MABG groups 3 weeks after 211At-MABG administration (P < 0.01). Thus, the 211At-MABG treatment groups showed significant tumor growth suppression compared to the control group (15 µCi: 9.6% ± 5.5% vs. control: 509.2% ± 169.1%, P < 0.01; 30 µCi: 3.3% ± 3.4% vs. control, P < 0.01). Although the 15- and 30-µCi 211At-MABG treatment groups temporarily had decreased body weight until day 3 (94% for 15 µCi and 84% for 30 µCi on day 3), it increased thereafter and recovered in approximately 10 days. In histological analysis, tumor sections of mice that received 30 µCi of 211At-MABG showed hemorrhage and lymphocytic infiltration on day 1. In addition, necrotic lesions were observed on day 3 with expanded area on day 7. In the 50-µCi- and 100-µCi-treated tumors on days 3 or 4, fibrosis was also observed. The 150-µCi-treated group showed loss of tumor cells on day 3 without hemorrhage. The fibrotic area tended to expand according to 211At-MABG dose.Conclusion: Administration of 15 and 30 µCi of 211At-MABG decreased tumor volumes until around 3 weeks and was tolerated in nude mice. Histological analysis showed 211At-MABG-induced hemorrhage and necrosis in PC-12 pheochromocytoma tumors. Therefore, the mechanisms of 211At-MABG may include tumor necrotic effects and tumor hemorrhage, suggesting that 211At-MABG has significantly histologically damaging effects. Therefore, 211At-MABG may have future clinical applications for the treatment of malignant pheochromocytoma.

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