Background: SHetA2 (NSC721689) is a non-toxic chemoprevention drug that has completed pre-clinical testing by the NCI-RAID and RAPID programs and will be evaluated in a Phase 0 clinical trial under development. Previous studies found that SHetA2 reversed the cancerous phenotype and prevented carcinogenesis in organotypic cultures of human ovarian cancer and endometrial cells. The objective of this project was to evaluate the effects of oral SHetA2 on histologic features of tumors induced by the nitrosomethylurea (MNU) carcinogen in Sprague-Dawley rats.

Methods: SHetA2 was administered to 3 treatment groups of 15 animals each in a Teklad diet formulated to contain doses of 0 (control), 25 (low dose) and 50 (high dose) mg/kg/day. Five days after initiation of treatment, each rat was injected with 11.25 mg of MNU into the peritoneum and the animals were continued on their respective diets. The first palpable tumors were noted 48 days after MNU injection. Tumors volumes were measured weekly. Four animals in the control group were euthanized early on days 58, 63, 78 and 82, one animal in the low dose group was euthanized on day 78 and one animal in the high dose group was euthanized on day 74 due to the excessive sizes of their tumors. The remaining animals were euthanized on day 85 and the tumors were collected for histologic evaluation. H&E stained slides of the tumors were reviewed for histologic features in a blinded manner. A linear mixed model was used to compare the growth rate of tumor volumes. The fixed effects included treatment group and days. An unstructured covariance matrix was used in the model. The numbers of mitoses in the tumors of the different treatment groups were compared using a linear mixed model.

Results: Tumor growth rate was significantly lower in the high dose group in comparison to the control group (p=.004) and the low dose (p=.003). No significant difference (p=.716) in growth rate was observed between low dose and control groups. The number of mitoses counted in the tumors was significantly smaller in the high dose than in the control group (p=.004), but no significant difference was observed between low dose and control groups (p=.945). The histology of the tumors included fibrocystic disease, intraductal papillomatosis, adenoid cystic carcinoma, papillary carcinoma, papillary and adenoid cystic carcinoma and carcinoma. When compared per animal, there were no significant differences in the histologies between the treatment groups, however when each tumor was considered an individual data point, there was a statistical trend that both doses of SHetA2 decreased the percentage of papillary carcinoma and increased the percentages of adenoid cystic carcinoma, (high dose vs control: p=.058; low dose vs control: p=.058).

Conclusion: SHetA2 administered in the diet reduced cell proliferation, growth and aggressiveness of the pathologic diagnosis of mammary tumors in MNU-treated rats.

Citation Format: Stan Lightfoot, Daniel Zhao, Elangovan Thavathiru, Doris Mangiaracina Benbrook. SHetA2 decreases mitoses and growth, and alters pathology of MNU-induced rat mammary tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3703. doi:10.1158/1538-7445.AM2013-3703