Differences in therapeutic indexes of combination metronomic chemotherapy and an anti-VEGFR-2 antibody in multidrug-resistant human breast cancer xenografts.
Differences in therapeutic indexes of combination metronomic chemotherapy and an anti-VEGFR-2 antibody in multidrug-resistant human breast cancer xenografts.
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发表时间：
2002
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通讯作者：
G. Klement;Ping Huang;B. Mayer;S. K. Green;S. Man;P. Bőhlen;D. Hicklin;R. Kerbel
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作者：
G. Klement;Ping Huang;B. Mayer;S. K. Green;S. Man;P. Bőhlen;D. Hicklin;R. Kerbel
化疗药物治疗癌症的最大障碍之一是获得耐药性。这包括由p -糖蛋白（Pgp）介导的对多种亲脂性天然化合物（如紫杉烷、阿霉素和长春花碱）的多重耐药。迄今为扭转这种和其他类型的耐药性所作的大量努力取得了非常有限的成功。我们在此报道，选择高水平Pgp和多药耐药的各种原位人乳腺癌异种移植物，当与抗血管内皮细胞生长因子（抗vegf）受体-2 （flk-1）中和抗体（DC101）联合使用时，对不同的连续低剂量（例如，最大耐受剂量的十分之一）化疗方案有显着和持久的反应。Pgp底物紫杉醇（紫杉醇）、阿霉素和长春花碱使用这种类型的联合治疗都有效，尽管化疗方案作为单一治疗显示很少或没有效果。使用顺铂（一种非pgp底物药物）治疗顺铂耐药肿瘤也获得了类似的结果。在肿瘤肿块未缩小的情况下，在开始治疗的3周内通过组织病理学分析发现联合治疗有明显的肿瘤细胞死亡的证据。然而，与微管蛋白抑制剂长春碱和紫杉醇相比，阿霉素和顺铂长期治疗方案的累积毒性有显著差异，在这些方案中观察到毒性。我们的结论是，血管靶向治疗方案包括频繁使用非常低剂量的某些化疗药物，只要这些药物与第二种抗血管生成药物（在这种情况下是抗vegfr -2阻断抗体）联合使用，就可以提供一种稳定和安全的方法来避免原位生长肿瘤的多药耐药。
One of the greatest barriers to the treatment of cancer with chemotherapeutic drugs is acquisition of drug resistance. This includes multidrug resistance mediated by P-glycoprotein (Pgp) to multiple lipophilic natural compounds such as taxanes, doxorubicin (Adriamycin), and vinblastine. The considerable efforts made thus far to reverse this and other types of drug resistance have had very limited success. We report here that a variety of orthotopic human breast cancer xenografts selected for high levels of Pgp and multidrug resistance respond in a significant and durable manner to different continuous low-dose (e.g., one-tenth the maximum tolerated dose of chemotherapy) chemotherapy regimens, when used in combination with an antivascular endothelial cell growth factor (anti-VEGF) receptor-2 (flk-1)-neutralizing antibody (DC101). The Pgp substrates paclitaxel (Taxol), Adriamycin, and vinblastine were all effective using this type of combination treatment, although the chemotherapy protocols showed little or no effect as monotherapies. Similar results were also obtained using cisplatinum (a non-Pgp substrate drug) against cisplatinum-resistant tumors. Evidence of significant tumor cell death by the combination treatment was detected within 3 weeks of initiation of therapy by histopathological analysis, in the absence of shrinkage of tumor mass. There were, however, marked differences in the cumulative toxicity of long-term regimens of Adriamycin and cisplatinum, where toxicity was observed, when compared with the tubulin inhibitors, vinblastine and Taxol, where it was not. We conclude that vascular-targeting protocols involving frequent administration of very low doses of certain chemotherapeutic drugs can provide a stable and safe way to circumvent multidrug resistance in established orthotopically growing tumors, as long as these are used in combination with a second antiangiogenic drug, in this case, anti-VEGFR-2 blocking antibodies.