Klement Giannoula, Huang Ping, Mayer Barbara, Green Shane K, Man Shan, Bohlen Peter, Hicklin Daniel, Kerbel Robert S
Sunnybrook and Women's College Health Sciences Centre, Molecular and Cellular Biology, Toronto, Ontario, M4N 3 M5 Canada.
Clin Cancer Res. 2002 Jan;8(1):221-32.
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.
使用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（多柔比星）和长春碱）的多药耐药性。迄今为止，为逆转这种和其他类型的耐药性所做的大量努力取得的成功非常有限。我们在此报告，多种因高水平Pgp和多药耐药性而被选择的原位人乳腺癌异种移植瘤，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，对不同的持续低剂量（例如，化疗最大耐受剂量的十分之一）化疗方案有显著且持久的反应。尽管化疗方案作为单一疗法几乎没有效果，但使用这种联合治疗方式时，Pgp底物紫杉醇（泰素）、阿霉素和长春碱均有效。使用顺铂（一种非Pgp底物药物）针对顺铂耐药肿瘤也获得了类似结果。通过组织病理学分析在治疗开始后3周内检测到联合治疗导致显著肿瘤细胞死亡的证据，此时肿瘤块并未缩小。然而，阿霉素和顺铂长期方案的累积毒性与未观察到毒性的微管蛋白抑制剂长春碱和泰素相比存在显著差异。我们得出结论，涉及频繁给予极低剂量某些化疗药物的血管靶向方案可以提供一种稳定且安全的方法来规避原位生长的既定肿瘤中的多药耐药性，只要这些方案与第二种抗血管生成药物（在这种情况下为抗VEGFR-2阻断抗体）联合使用。
