Abstract 4464: Growth inhibitory effect of combination of sorafenib and IFNα using a new drug delivery system
Authors: Ueda Kosuke , Akiba Jun , Ogasawara Sachiko , Todoroki Keita , Nakayama Masamichi , Sumi Akiko , Kusano Hironori , Sanada Sakiko , Suekane Shigetaka , Xu Keming , Kurisawa Motoichi , Matsuoka Kei , Yano Hirohisa 
Published: May 2015

Abstract
Background: Immunotherapy including IFNα is one of the treatment options for metastatic renal cell carcinoma (mRCC) patients, especially Japanese mRCC patients. Recent reports showed that IFNα not only has direct antitumor and anti-angiogenic activity, but also enhances the anti-tumor and anti-angiogenic effects of sorafenib. Despite clinical benefits for the selected patients, IFNα therapy has some problems, such as poor tolerability and dose-limiting adverse effects. In addition, the frequent injections reduce a patient's quality of life and compliance. Recently, an injectable and biodegradable hydrogel system to prolong drug release is reported. The hydrogel system has demonstrated that IFNα2a-incorporated hydrogels inhibit the tumor growth more than IFNα2a solution alone. In this study, we evaluated the synergistic efficacy of IFNα-incorporated Hyaloronic acid-Tyramine (HA-Tyr) hydrogels and sorafenib in tumor regression.
Material and Methods: We used a RCC cell line, ACHN. ACHN cells (5×106 cells) were subcutaneously injected to the back of 5-week-old female BALB/c nude mice. Each group (n=8) was assigned to one of the five treatments: 1) control; 2) IFNα alone; 3) sorafenib alone; 4) IFNα + sorafenib; 5) IFNα-incorporated HA-Tyr hydrogels + sorafenib. IFNα (4,000 IU) and IFNα (4,000 IU)-incorporated HA-Tyr hydrogels were injected subcutaneously twice a week (Day 1, 4, 8 and 11), and sorafenib (200 µg/day) was given orally every day for 2 weeks. Tumor volume was monitored during the experiment. On Day 15, the mice were sacrificed and the tumors were resected and weighed. Proliferative activity and presence of apoptosis of the tumors were examined by Ki-67 immunostain and TUNEL assay.
Results: The tumor volume of mice that received IFNα, sorafenib, IFNα + sorafenib, IFNα-incorporated HA-Tyr hydrogels + sorafenib was 85, 74, 67 and 53%, respectively, of the control and the tumor weight was 94, 86, 89 and 55 %, respectively, of the control. There was a significant difference in tumor weight between IFNα-incorporated HA-Tyr hydrogels + sorafenib and IFNα + sorafenib (p&lt;0.05). Ki-67 labeling index was significantly lower in the IFNα-incorporated HA-Tyr hydrogels + sorafenib treatment group than in the other groups. In addition, apoptotic cells were significantly higher in the IFNα-incorporated HA-Tyr hydrogels + sorafenib treatment group than in the other group.
Conclusion: Our results suggest a possibility that HA-Tyr hydrogel drug delivery system prolongs the biological half-life of natural human
IFNα and enhances its anticancer effects on human RCC cells.
Citation Format: Kosuke Ueda, Jun Akiba, Sachiko Ogasawara, Keita Todoroki, Masamichi Nakayama, Akiko Sumi, Hironori Kusano, Sakiko Sanada, Shigetaka Suekane, Keming Xu, Motoichi Kurisawa, Kei Matsuoka, Hirohisa Yano. Growth inhibitory effect of combination of sorafenib and IFNα using a new drug delivery system. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4464. doi:10.1158/1538-7445.AM2014-4464