Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer.
Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer.
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发表时间：
2000-04
期刊：
影响因子：
11.2
通讯作者：
T. Browder;C. Butterfield;B. Kräling;B. Shi;B. Marshall;M. O’Reilly;J. Folkman
中科院分区：
文献类型：
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作者：
T. Browder;C. Butterfield;B. Kräling;B. Shi;B. Marshall;M. O’Reilly;J. Folkman
为了揭示癌症化疗的抗血管生成能力，我们开发了一种替代环磷酰胺给药的抗血管生成方案。我们在这里表明，这种抗血管生成的时间表避免了耐药性和根除刘易斯肺癌和L1210白血病，结果不可能与传统的时间表。当刘易斯肺癌和EMT-6乳腺癌在治疗前产生耐药性时，抗血管生成方案抑制肿瘤生长的效果是常规方案的3倍。当另一种血管生成抑制剂TNP-470加入到环磷酰胺的抗血管生成方案中时，耐药的刘易斯肺癌被根除。环磷酰胺的抗血管生成方案的每个剂量诱导肿瘤内的内皮细胞的凋亡，并且内皮细胞凋亡先于耐药肿瘤细胞的凋亡。这种抗血管生成作用在p53缺失小鼠中更为明显，其中环磷酰胺诱导的p53缺失内皮细胞的凋亡是如此强烈，以至于包括4.5%体重的耐药肿瘤被根除。因此，通过使用环磷酰胺的给药方案，提供了更持久的肿瘤血管床内的内皮细胞凋亡，我们表明，化疗剂可以更有效地控制肿瘤生长的小鼠，无论肿瘤细胞是否耐药。
To reveal the antiangiogenic capability of cancer chemotherapy, we developed an alternative antiangiogenic schedule for administration of cyclophosphamide. We show here that this antiangiogenic schedule avoided drug resistance and eradicated Lewis lung carcinoma and L1210 leukemia, an outcome not possible with the conventional schedule. When Lewis lung carcinoma and EMT-6 breast cancer were made drug resistant before therapy, the antiangiogenic schedule suppressed tumor growth 3-fold more effectively than the conventional schedule. When another angiogenesis inhibitor, TNP-470, was added to the antiangiogenic schedule of cyclophosphamide, drug-resistant Lewis lung carcinomas were eradicated. Each dose of the antiangiogenic schedule of cyclophosphamide induced the apoptosis of endothelial cells within tumors, and endothelial cell apoptosis preceded the apoptosis of drug-resistant tumor cells. This antiangiogenic effect was more pronounced in p53-null mice in which the apoptosis of p53-null endothelial cells induced by cyclophosphamide was so vigorous that drug-resistant tumors comprising 4.5% of body weight were eradicated. Thus, by using a dosing schedule of cyclophosphamide that provided more sustained apoptosis of endothelial cells within the vascular bed of a tumor, we show that a chemotherapeutic agent can more effectively control tumor growth in mice, regardless of whether the tumor cells are drug resistant.