Abstract 4256: Antitumor activity of capecitabine in combination with bevacizumab and cyclophosphamide in triple-negative breast cancer xenograft model
Authors: Yanagisawa Mieko , Yorozu Keigo , Satoh Fumi , Kurasawa Mitsue , Yamamoto Kaname , Fujimoto-Ouchi Kaori 
Published: July 2012

Abstract
Objective: Triple-negative (ER-/PR-/HER2-) breast cancer (TNBC) is associated with a poor prognosis. Combination therapy with capecitabine (Cape) and bevacizumab (BV) has been reported to improve the progression-free survival of breast cancer patients (Robert NJ et al. ASCO 2009; RIBBON-1). In addition, Cape plus cyclophosphamide (CPA) combination therapy is considered to be effective for metastatic breast cancer patients (Tanaka M et al. Anticancer Drugs 2010). These findings prompted us to examine the antitumor efficacy of Cape+BV+CPA combination therapy in a TNBC xenograft model. Materials and Methods: MX-1 human TNBC cells were subcutaneously inoculated into the right flank of BALB-nu/nu mice. Treatment began (day 1) when tumor volume reached approximately 200 mm3. The mice were given Cape (359 mg/kg) and CPA (10 mg/kg) orally, 14 days on and 7 days off. BV (5 mg/kg) was administered intraperitoneally every 7 days for 3 weeks. Tumor volumes (mm3) were monitored twice a week and antitumor activity was evaluated on day 22. Six mice were allotted to each group (Cape+BV+CPA, Cape+BV, Cape+CPA, CPA, BV, control). Thymidine phosphorylase (TP: U/mg protein) levels in the tumor were measured by ELISA methods on day 15. Microvessel density (MVD, %) in tumor tissue was determined using CD31 immunohistochemical staining method on day 15. MVD% was calculated as the ratio of the CD31-positive staining area to the total observation area in the viable region. Results and Discussion: The antitumor activity of Cape+BV+CPA was significantly higher than that of Cape+BV or CPA (p≤0.05) and was also significantly stronger than that of Cape+CPA or BV (p≤0.05). The tumor volume on day 22 was as follows: control, 3969±1026; BV group, 2219±410; CPA group, 2149±962; Cape+BV group, 1270±458; Cape+CPA group, 1534±133; Cape+BV+CPA group, 536±261. The TP levels of the CPA (11.6±2.62), BV (6.21±2.59) and BV+CPA (13.1±2.70) groups were significantly increased compared to the control group (3.77±0.883, p≤0.05). The TP levels of the BV+CPA group were significantly higher than those of the BV group. (p≤0.05). The MVD% of BV (1.92±0.385), Cape+BV (1.26±0.347) and Cape+BV+CPA (1.00±0.160) was significantly decreased compared to the control group (3.57±0.343, p≤0.05). The MVD of the Cape+BV+CPA group was significantly depressed compared to that of the Cape+CPA (3.27±0.578), p≤0.05) group. These results indicate that 5-FU converted from Cape was increased by up-regulated TP with CPA, that it caused antitumor activity of Cape+BV+CPA superior to Cape+BV. BV significantly reduced MVD either alone or in the triplet combination (Cape+BV+CPA) and it is considered to result in the greatest effect in the triplet combination. Conclusion: Our preclinical results suggest that the Cape+BV+CPA (XAC) combination may be a rational therapy to be explored in TNBC patients.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4256. doi:10.1158/1538-7445.AM2011-4256