Abstract 1389: Low dose metronomic chemotherapy of S-1 and Vandetanib produces nontoxically good therapeutic results for hepatocellular carcinoma (HCC)
Authors: Hideki Iwamoto , Torimura Takuji , Nakamura Toru , Ueno Takato , Yano Hirohisa , Sata Michio 
Published: February 2011

Abstract
[Background and aim] A conventional chemotherapy for cancer, which is administered at the maximum tolerated dose (MTD), requires a break period to avoid adverse toxic events. The breaks sometimes allow tumor regrowth. On the other hand, low dose metronomic chemotherapy (LDM) means frequent low dose administration of the cytotoxic agent without breaks. Here, we investigated the therapeutic efficacies of LDM using S-1, a novel 5-FU based drug, and with Vandetanib (VEGFR-2 and EGFR inhibitors), an anti-angiogenic agent.
[Materials and Methods] The inhibitory effects of 5-FU on the proliferation of HUVEC and human hepatoma cell lines were evaluated in vitro. We compared the anti-tumor effect, toxicity and survival in the following 6 groups; MTD and LDM using S-1, Vandetanib (25 mg/kg/day), S-1 MTD + Vandetanib and S-1 LDM + Vandetanib. In the S-1 MTD group, mice were administered orally at 15 mg/kg/day for 7 days followed by a break for 7 days. In the S-1 LDM group, S-1 of 5mg/kg/day was consecutively administered once a day without a break. In the subcutaneous tumor model, tumor volumes and toxicities were evaluated. In the liver xenograft model, tumor volumes and survival were evaluated. Micro vessel density (MVD) in tumor tissues was evaluated by immunohistochemistry using an anti CD-31 antibody. The expression of VEGF and thrombospondin-1 (an endogeneous anti-angiogenic factor: TSP-1) was analysed by Western blot.
[Results] Cell proliferation of HUVEC and hepatoma cell lines was inhibited at apparently lower doses in the metronomic schedule compared with the MTD schedule. In the subcutaneous tumor model, S-1 LDM significantly inhibited tumor growth (control: 4,810 ± 1,440 mm3, S-1 MTD: 3,212 ± 1,364 mm3, S-1 LDM: 1,927 ± 652 mm3) and its effect was enhanced by the combination with Vandetanib (LDM S-1 + Vandetanib: 1,383 ± 697 mm3). In toxicities, S-1 MTD caused severe body weight loss, and myelo-suppression. On the other hand, S-1 LDM did not show any toxicities. In the liver xenograft model, S-1 LDM and the combination therapy with Vandetanib significantly inhibited tumor growth and S-1 LDM apparently prolonged survival (control: 28.9 ± 6.4 days, S-1 MTD: 29.6 ± 3.9 days, S-1 LDM: 34.3 ± 3.9 days). S-1 LDM + Vandetanib showed the most prolonged survival (49.6 ± 11.5 days). MVDs in the tumor of control, S-1 MTD, S-1 LDM, S-1 LDM + Vandetanib were 41.1 ± 9.2 /field, 35.8 ± 5.5 /field, 17.2 ± 4.1 /field, and 8.2 ± 1.6 /field, respectively. The expression of VEGF and TSP-1 was strongly upregulated in S-1 LDM group and S-1 LDM + Vandetanib group.
[Conclusion] S-1 LDM significantly suppressed tumor growth and prolonged survival without severe toxicities. These anti-tumor effects were enhanced by the combination therapy with Vandetanib. These results indicate that S-1 LDM with an anti-angiogenic agent will become a novel therapeutic strategy for human hepatocellular carcinoma.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1389.