Combination Therapy of Capecitabine with Cyclophosphamide as a Second-Line Treatment after Failure of Paclitaxel plus Bevacizumab Treatment in a Human Triple Negative Breast Cancer Xenograft Model

Mieko Yanagisawa, Keigo Yorozu, Mitsue Kurasawa, Yoichiro Moriya, Naoki Harada

Product Research Department, Chugai Pharmaceutical Co., Ltd., Kamakura, Japan.

DOI: 10.4236/jct.2013.47144                

Abstract

We examined the antitumor efficacy of the capecitabine (CAPE) plus cyclophosphamide (CPA) combination as a 2^nd-line therapy after paclitaxel (PTX) plus bevacizumab (BEV) treatment in a xenograft model of human triple negative breast cancer (TNBC) cell line, MX-1. After tumor growth was confirmed, PTX (20 mg/kg; i.v.) + BEV (5 mg/kg; i.p.) treatment was started (Day 1). Each agent was administered once a week for 5 weeks and tumor regression was observed for at least the first 3 weeks. For 2^nd-line treatment, we selected mice in which the tumor volume had increased from day 29 to day 36 and was within 130 - 250 mm³ on day 36. After randomization of mice selected on day 36, CPA (10 mg/kg; p.o.) and CAPE (539 mg/kg; p.o.) were administered daily for 14 days (days 36 - 49), followed by cessation of the drugs for 1 week. The tumor growth on day 57 was significantly suppressed in the CPA, CAPE and CAPE + CPA groups as compared with the control group (p < 0.05). Furthermore, the antitumor activity on day 57 of CAPE + CPA was significantly stronger than that of CPA or CAPE alone (p < 0.05). The thymidine phosphorylase (TP) level in tumor tissue was evaluated by immunohistochemistry on day 50, and was significantly higher in the CPA group than those in the control group (p < 0.05). Upregulation of TP in tumor tissues by CPA treatment would increase the 5-FU level in tumor tissues treated with CAPE. This would explain the possible mechanism that made CAPE + CPA superior to CAPE alone in the 2^nd-line treatment. Our preclinical results suggest that the CAPE + CPA combination therapy may be effective as 2^nd-line therapy after disease progression in PTX + BEV 1^st-line treatment for TNBC patients.

Keywords

Triple Negative Breast Cancer; Capecitabine; Cyclophosphamide; Bevacizumab; Paclitaxel; Xenograft Model

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	L. G. Presta, H. Chen, S. J. O’Connor, V. Chisholm, Y. G. Meng, et al., “Humanization of an Anti-Vascular Endothelial Growth Factor Monoclonal Antibody for the Therapy of Solid Tumors and Other Disorders,” Cancer Research, Vol. 57, No. 20, 1997, pp. 4593-4599.
[2]	K. J. Kim, B. Li, K. Houck, J. Winer and N. Ferrara, “The Vascular Endothelial Growth Factor Proteins: Identification of Biologically Relevant Regions by Neutralizing Monoclonal Antibodies,” Growth Factors, Vol. 7, No.1, 1992, pp. 53-64. doi:10.3109/08977199209023937
[3]	Y. Wang, D. Fei, M. Vanderlaan and A. Song, “Biological Activity of Bevacizumab, a Humanized Anti-Vegf Antibody in Vitro,” Angiogenesis, Vol. 7, No. 4, 2004, pp. 335-345. doi:10.1007/s10456-004-8272-2
[4]	K. J. Kim, B. Li, J. Winer, M. Armanini, N. Gillett, et al., “Inhibition of Vascular Endothelial Growth Factor-Induced Angiogenesis Suppresses Tumour Growth in Vivo,” Nature, Vol. 362, No. 6423, 1993, pp. 841-844. doi:10.1038/362841a0
[5]	H. P. Gerber and N. Ferrara, “Pharmacology and Pharmacodynamics of Bevacizumab as Monotherapy or in Combination with Cytotoxic Therapy in Preclinical Studies,” Cancer Research, Vol. 65, No. 3, 2005, pp. 671-680.
[6]	P. V. Dickson, J. B. Hamner, T. L. Sims, C. H. Fraga, C. Y. Ng, et al., “Bevacizumab-Induced Transient Remodeling of the Vasculature in Neuroblastoma Xenografts Results in Improved Delivery and Efficacy of Systemically Administered Chemotherapy,” Clinical Cancer Research, Vol. 13, No. 13, 2007, pp. 3942-3950. doi:10.1158/1078-0432.CCR-07-0278
[7]	M. Yanagisawa, K. Fujimoto-Ouchi, K. Yorozu, Y. Yamashita and K. Mori, “Antitumor Activity of Bevacizumab in Combination with Capecitabine and Oxaliplatin in Human Colorectal Cancer Xenograft Models,” Oncology Reports, Vol. 22, No. 2, 2009, pp. 241-247.
[8]	M. Yanagisawa, K. Yorozu, M. Kurasawa, K. Nakano, K. Furugaki, et al., “Bevacizumab Improves the Delivery and Efficacy of Paclitaxel,” Anticancer Drugs, Vol. 21, No. 7, 2010, pp. 687-694.
[9]	Y. Yamashita-Kashima, K. Fujimoto-Ouchi, K. Yorozu, M. Kurasawa, M. Yanagisawa, et al., “Biomarkers for Antitumor Activity of Bevacizumab in Gastric Cancer Models,” BMC Cancer, Vol. 12, 2012, p. 37. doi:10.1186/1471-2407-12-37
[10]	S. B. Horwitz, “Mechanism of Action of Taxol,” Trends in Pharmacological Sciences, Vol. 13, No. 4, 1992, pp. 134-136. doi:10.1016/0165-6147(92)90048-B
[11]	K. Miller, M. Wang, J. Gralow, M. Dickler, M. Cobleigh, et al., “Paclitaxel plus Bevacizumab versus Paclitaxel Alone for Metastatic Breast Cancer,” New England Journal of Medicine, Vol. 357, No. 26, 2007, pp. 2666-2676. doi:10.1056/NEJMoa072113
[12]	M. Tanaka, Y. Takamatsu, K. Anan, S. Ohno, R. Nishimura, et al., “Oral Combination Chemotherapy with Capecitabine and Cyclophosphamide in Patients with Metastatic Breast Cancer: A Phase II Study,” Anti-Cancer Drugs, Vol. 21, No. 4, 2010, pp. 453-458. doi:10.1097/CAD.0b013e328336acb1
[13]	H. Yasuno, M. Kurasawa, M. Yanagisawa, Y. Sato, N. Harada, et al., “Predictive Markers of Capecitabine Sensitivity Identified from the Expression Profile of Pyrimidine Nucleoside-Metabolizing Enzymes,” Oncology Reports, Vol. 29, No. 2, 2013, pp. 451-458.
[14]	T. Ishikawa, F. Sekiguchi, Y. Fukase, N. Sawada and H. Ishitsuka, “Positive Correlation between the Efficacy of Capecitabine and Doxifluridine and the Ratio of Thymidine Phosphorylase to Dihydropyrimidine Dehydrogenase Activities in Tumors in Human Cancer Xenografts,” Cancer Research, Vol. 58, No. 4, 1998, pp. 685-690.
[15]	M. Endo, N. Shinbori, Y. Fukase, N. Sawada, T. Ishikawa, et al., “Induction of Thymidine Phosphorylase Expression and Enhancement of Efficacy of Capecitabine or 5’-Deoxy-5-Fluorouridine by Cyclophosphamide in Mammary Tumor Models,” International Journal of Cancer, Vol. 83, No. 1, 1999, pp. 127-134. doi:10.1002/(SICI)1097-0215(19990924)83:1<127::AID-IJC22>3.0.CO;2-6
[16]	N. Sawada, T. Ishikawa, Y. Fukase, M. Nishida, T. Yoshikubo, et al., “Induction of Thymidine Phosphorylase Activity and Enhancement of Capecitabine Efficacy by Taxol/Taxotere in Human Cancer Xenografts,” Clinical Cancer Research, Vol. 4, No. 4, 1998, pp. 1013-1019.
[17]	J. Cassidy, J. Tabernero, C. Twelves, R. Brunet, C. Butts, et al., “Xelox (Capecitabine plus Oxaliplatin): Active First-Line Therapy for Patients with Metastatic Colorectal Cancer,” Journal of Clinical Oncology, Vol. 22, No. 11, 2004, pp. 2084-2091. doi:10.1200/JCO.2004.11.069
[18]	N. Sawada, K. Kondoh and K. Mori, “Enhancement of Capecitabine Efficacy by Oxaliplatin in Human Colorectal and Gastric Cancer Xenografts,” Oncology Reports, Vol. 18, No. 4, 2007, pp. 775-778.
[19]	K. Fujimoto-Ouchi, M. Yanagisawa, F. Sekiguchi and Y. Tanaka, “Antitumor Activity of Erlotinib in Combination with Capecitabine in Human Tumor Xenograft Models,” Cancer Chemotherapy and Pharmacology, Vol. 57, No. 5, 2006, pp. 693-702. doi:10.1007/s00280-005-0079-3
[20]	N. Sawada, T. Ishikawa, F. Sekiguchi, Y. Tanaka and H. Ishitsuka, “X-Ray Irradiation Induces Thymidine Phosphorylase and Enhances the Efficacy of Capecitabine (Xeloda) in Human Cancer Xenografts,” Clinical Cancer Research, Vol. 5, 1999, pp. 2948-2953.
[21]	E. Mechetner, A. Kyshtoobayeva, S. Zonis, H. Kim, R. Stroup, et al., “Levels of Multidrug Resistance (mdr1) p-Glycoprotein Expression by Human Breast Cancer Correlate with in Vitro Resistance to Taxol and Doxorubicin,” Clinical Cancer Research, Vol. 4, 1998, pp. 389-398.
[22]	J. P. de Hoon, J. Veeck, B. E. Vriens, T. G. Calon, M. van Engeland, et al., “Taxane Resistance in Breast Cancer: A Closed Her2 Circuit?” Biochimica et Biophysica Acta, Vol. 1825, No. 2, 2012, pp. 197-206.
[23]	A. K. Koutras, I. Starakis, U. Kyriakopoulou, P. Katsaounis, A. Nikolakopoulos, et al., “Targeted Therapy in Colorectal Cancer: Current Status and Future Challenges,” Current Medicinal Chemistry, Vol. 18, No. 11, 2011, pp. 1599-1612. doi:10.2174/092986711795471338
[24]	S. Tejpar, H. Prenen and M. Mazzone, “Overcoming Resistance to Antiangiogenic Therapies,” Oncologist, Vol. 17, No. 8, 2012, pp. 1039-1050. doi:10.1634/theoncologist.2012-0068
[25]	N. Ferrara and R. S. Kerbel, “Angiogenesis as a Therapeutic Target,” Nature, Vol. 438, No. 7070, 2005, pp. 967-974. doi:10.1038/nature04483
[26]	M. F. Mulcahy, “Bevacizumab in the Therapy for Refractory Metastatic Colorectal Cancer,” Biologics, Vol. 2, No. 1, 2008, pp. 53-59.