Comparative impact of trastuzumab and cyclophosphamide on HER-2-positive human breast cancer xenografts.
Comparative impact of trastuzumab and cyclophosphamide on HER-2-positive human breast cancer xenografts.
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DOI：
10.1158/1078-0432.ccr-09-0931
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发表时间：
2009-10-15
期刊：
影响因子：
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通讯作者：
Kerbel RS
中科院分区：
文献类型：
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作者：
Francia G;Man S;Lee CJ;Lee CR;Xu P;Mossoba ME;Emmenegger U;Medin JA;Kerbel RS
节拍化疗是一种毒性最小且经常有效的新治疗策略，其开始显示出有希望的II期临床试验结果，特别是与各种分子靶向抗肿瘤药物联合治疗转移性乳腺癌时。在这里，我们评估了使用曲妥珠单抗加每日口服节拍环磷酰胺治疗转移性Her-2阳性人乳腺癌模型的治疗策略。对原位移植的原发性肿瘤以及两个独立的Her-2阳性乳腺癌模型的已建立的内脏转移性疾病开始治疗，这两个模型均独立地源自人MDA-MB-231乳腺癌细胞系。通过非侵入性测量尿液中肿瘤细胞分泌的人绒毛膜促性腺激素作为相对肿瘤负荷的替代标志物，或通过全身生物发光成像，以及生存期的延长来评估结局。原位原发性肿瘤对曲妥珠单抗单药治疗有显著的生长延迟反应，而对转移性疾病小鼠进行治疗时观察到的抗肿瘤作用极小。尽管如此，曲妥珠单抗与节律性低剂量环磷酰胺联合使用时，在后一种情况下显示出获益，通过延长生存期进行评估。这种获益与曲妥珠单抗加最大耐受剂量环磷酰胺相似，但毒性较小。曲妥珠单抗联合节拍环磷酰胺可能是治疗Her-2阳性转移性乳腺癌的有效长期维持策略。
Metronomic chemotherapy is a minimally toxic and frequently effective new treatment strategy that is beginning to show promising phase II clinical trial results, particularly for metastatic breast cancer when combined with various molecularly targeted antitumor agents. Here, we assessed a treatment strategy that uses trastuzumab plus daily oral metronomic cyclophosphamide on metastatic Her-2–positive human breast cancer models. Treatments were initiated on orthotopic transplanted primary tumors as well as established visceral metastatic disease of two independent Her-2–positive breast cancer models, both independently derived from the human MDA-MB-231 breast cancer cell line. Outcome was assessed by noninvasive measurements of tumor cell–secreted human choriogonadotropin in the urine as a surrogate marker of relative tumor burden, or by whole body bioluminescent imaging, in addition to prolongation of survival. Orthotopic primary tumors responded to trastuzumab monotherapy with significant growth delays, whereas minimal antitumor effect was observed when mice with metastatic disease were treated. Nevertheless, trastuzumab showed a benefit in this latter setting when combined with metronomic low-dose cyclophosphamide as assessed by prolongation of survival. This benefit was similar to trastuzumab plus maximum tolerated dose cyclophosphamide, but was associated with lesser toxicity. Trastuzumab combined with metronomic cyclophosphamide may be an effective long-term maintenance strategy for the treatment of Her-2–positive metastatic breast cancer.