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 — Oak Academic Publishing
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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
Product Research Department, Chugai Pharmaceutical Co., Ltd., Kamakura, Japan
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Product Research Department, Chugai Pharmaceutical Co., Ltd., Kamakura, Japan
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Product Research Department, Chugai Pharmaceutical Co., Ltd., Kamakura, Japan
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Product Research Department, Chugai Pharmaceutical Co., Ltd., Kamakura, Japan
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Product Research Department, Chugai Pharmaceutical Co., Ltd., Kamakura, Japan
1 Product Research Department, Chugai Pharmaceutical Co., Ltd., Kamakura, Japan
2 Product Research Department, Chugai Pharmaceutical Co., Ltd., Kamakura, Japan
3 Product Research Department, Chugai Pharmaceutical Co., Ltd., Kamakura, Japan
4 Product Research Department, Chugai Pharmaceutical Co., Ltd., Kamakura, Japan
5 Product Research Department, Chugai Pharmaceutical Co., Ltd., Kamakura, Japan
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 mm 3 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 effe c tive as 2 nd -line therapy after disease progression in PTX + BEV 1 st -line treatment for TNBC patients .
KeywordsTriple Negative Breast CancerCapecitabineCyclophosphamideBevacizumabPaclitaxelXenograft Model
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