Abstract 2408: Melatonin action in xenograft model of breast cancer, comparing radiopharmaceuticals in the detection of intratumor heterogeneity by PET/CT confirmed by immunohistochemical markers
Authors: Mota André L. , Jardim-Perassi Bruna V. , Borin Thaiz F. , Sonehara Nathália M. , Pozzo Lorena , Bernardes Emerson S. , Cogliati Bruno , Zuccari Debora APC 
Published: July 2016

Abstract
Breast cancer is the most common cancer among women and has a high mortality rate. The rapid tumor growth makes difficult the perfusion of O2 mainly in the tumor center, and this hypoxia in tumor microenvironment can exerts selective pressure on the tumor cells, selecting subpopulations with advantage for survival in adverse conditions, characterizing the intratumor heterogeneity. In this context, melatonin, a hormone naturally produced by the pineal gland, has shown antitumor activity, as immunomodulatory, antioxidant, pro-apoptotic, anti-proliferative, antimetastatic, antiangiogenic and with potencial effects in intratumor heterogeneity. The aims of this study was to evaluate the effectiveness of melatonin in a xenograft model of breast cancer, focusing on intratumor heterogeneity verified by PET/CT and by immunohistochemical markers of hypoxia. The tumors were developed by the implantation of 5 million triple-negative breast cancer cells (MDA-MB-231) into the flank of female Balb/c nude mice (n = 14). Treatment with melatonin (n = 7) or vehicle (n = 7) was initiated 10 days after tumor implantation and continued for 14 days. At the end, micro-PET/CT scanning was performed with 18F-FDG, which is an analogue of glucose, and with 18F-FAZA, a specific radiopharmaceutical for hypoxia detection. The radiopharmaceuticals were injected by retro-orbital via and the images were acquired using Albira PET/SPECT/CT Carestream Molecular Imaging. Then, markers of hypoxia were evaluated by immunohistochemistry in mammary tumors. The results showed that tumor growth in animals treated with melatonin was lower than those treated with vehicle (p&lt;0.05). There was tumor regression in one animal treated with melatonin, showing 18.72 mm3 at start of treatment and no longer being detected after seven days of treatment. 18F-FDG can be used as hypoxia marker, however, studies show that can occurs overlapping areas of aerobic and anaerobic glycolysis in the tumor, difficulting the identification of hypoxic areas. 18F-FAZA has a hypoxia-specific uptake mechanism and a better spread by the tumor. Results of PET/CT showed that 18F-FDG had homogeneous uptake in breast tumors. In some tumors with high volume, there was no uptake in the tumor center, corresponding to areas of necrosis. In addition, there was an intratumor 18F-FAZA uptake heterogeneity, indicating possible hypoxic areas. Also, PET/CT results showed that there was less hypoxic areas in animals treated with melatonin, which was confirmed by immunohistochemical markers. Taken together, our results showed an important action of melatonin, in control of mammary tumor growth, decreasing hypoxia areas and controlling cancer progression. Financial support: Fundação de Amparo à Pesquisa do Estado de São Paulo
Citation Format: André L. Mota, Bruna V. Jardim-Perassi, Thaiz F. Borin, Nathália M. Sonehara, Lorena Pozzo, Emerson S. Bernardes, Bruno Cogliati, Debora APC Zuccari. Melatonin action in xenograft model of breast cancer, comparing radiopharmaceuticals in the detection of intratumor heterogeneity by PET/CT confirmed by immunohistochemical markers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2408.