Central Research Laboratory, The Affiliated Hospital of Qingdao University, Qingdao 266071, China.
Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden.
Proc Natl Acad Sci U S A. 2017 Jun 27;114(26):E5226-E5235. doi: 10.1073/pnas.1705066114. Epub 2017 Jun 12.
Long-term uninterrupted therapy is essential for maximizing clinical benefits of antiangiogenic drugs (AADs) in cancer patients. Unfortunately, nearly all clinically available AADs are delivered to cancer patients using disrupted regimens. We aim to develop lifetime, nontoxic, effective, orally active, and low-cost antiangiogenic and antitumor drugs for treatment of cancer patients. Here we report our findings of long-term maintenance therapy with orally active, nontoxic, low cost antiangiogenic chemotherapeutics for effective cancer treatment. In a sequential treatment regimen, robust antiangiogenic effects in tumors were achieved with an anti-VEGF drug, followed by a low-dose chemotherapy. The nontoxic, low dose of the orally active prodrug capecitabine was able to sustain the anti-VEGF-induced vessel regression for long periods. In another experimental setting, maintenance of low-dose capecitabine produced greater antiangiogenic and antitumor effects after AAD plus chemotherapy. No obvious adverse effects were developed after more than 2-mo of consecutive treatment with a low dose of capecitabine. Together, our findings provide a rationalized concept of effective cancer therapy by long-term maintenance of AAD-triggered antiangiogenic effects with orally active, nontoxic, low-cost, clinically available chemotherapeutics.
长期不间断治疗对于最大限度地提高癌症患者抗血管生成药物（AAD）的临床获益至关重要。不幸的是，几乎所有临床可用的 AAD 都是通过中断方案为癌症患者提供的。我们旨在开发用于治疗癌症患者的终生、无毒、有效、口服活性和低成本的抗血管生成和抗肿瘤药物。在这里，我们报告了我们使用口服活性、无毒、低成本的抗血管生成化疗药物进行长期维持治疗以有效治疗癌症的发现。在序贯治疗方案中，使用抗 VEGF 药物实现了肿瘤中强大的抗血管生成作用，然后进行低剂量化疗。口服活性前药卡培他滨的无毒、低剂量能够长时间维持抗 VEGF 诱导的血管消退。在另一个实验环境中，在 AAD 加化疗后，低剂量卡培他滨的维持产生了更大的抗血管生成和抗肿瘤作用。连续使用低剂量卡培他滨超过 2 个月后，没有明显的不良反应。总之，我们的发现为通过口服活性、无毒、低成本、临床可用的化疗药物长期维持 AAD 触发的抗血管生成作用来有效治疗癌症提供了合理化的概念。
