2014-08-012024-05-18https://scholars.lib.ntu.edu.tw/handle/123456789/704953摘要：抑制腫瘤血管新生作為癌症治療的標的一直是幾十年來熱門的研究議題。雖然單獨使用抑制腫瘤血管新生的藥物在絕大部分種類的癌症的治療成績是令人失望的，化學治療藥物合併抑制腫瘤血管新生的藥物，特別是 bevacizumab (癌思停)，一種抑制 VEGFA(一般腫瘤細胞會分泌此促血管新生因子)的單株抗體，在初步臨床試驗中獲致了令人振奮的成功，因此獲得乳癌及大腸癌的治療適應症。然而，後續的臨床試驗卻無法複製先前研究的成功經驗，因此美國食品藥物管理局撤銷癌思停治療乳癌之適應症。此一結果對於抑制腫瘤血管新生的研究與發展造成嚴重的打擊。腫瘤血管的特色是扭曲，擴張，高通透滲漏，因而造成組織缺氧以及高組織間質壓，造成化學治療藥物不易進入腫瘤以及抗藥性。動物實驗發現，抑制腫瘤血管新生藥物的治療會暫時誘發腫瘤血管的正常化，對腫瘤而言血流灌注反而改善。因此，抑制腫瘤血管新生藥物合併化學治療時能因為血流的改善而有效增加腫瘤藥物濃度，以及透過改善缺氧狀態而減少抗藥性。然而，此血管正常化的效應是暫時的，一段時間之後腫瘤血管又恢復原狀。我們推論，如果要以誘發腫瘤血管正常化做為組合性治療的學理基礎，抑制腫瘤血管新生藥物的給予應該在化學治療之前有一段合理的時間間隔，而非如目前制式標準同一天陸續給予。我們初步的研究結果發現，不論是對於過去研究癌思停第三期臨床試驗的統合分析(meta-analysis)，動物試驗，以及依此原則設計新的療程，進行的一項針對乳癌合併腦轉移患者的臨床試驗初步前瞻性臨床試驗結果，皆支持此假說。另外，我們的初步實驗室研究發現，乳癌細胞與大腦的星狀細胞共同培養，會增加乳癌細胞對化學治療的抗藥性，而癌思停的治療可部分逆轉此一現象。我們並發現，VEGFA會促進星狀細胞製造多種癌細胞生長因子與細胞激素。因此另一個可能的假說是，癌思婷可能會透過阻斷癌細胞分泌的 VEGF作用於星狀細胞表面的 VEGF受體，改變癌細胞與在大腦的微環境的互動，進而改善對化療藥物的敏感性。 此研究的目的是(1)尋找抑制腫瘤血管新生藥物與化學治療的組合在轉移性癌症治療的最佳化模式與機轉，並找出抑制腫瘤血管新生藥物誘發癌症腫瘤血管正常化效應的最佳化學治療藥物使用期間；(2) 探索抑制腫瘤血管新生藥物是否可能透過阻斷癌細胞與微環境中正常細胞之間的互動來改善抗藥性，而且在不同器官組織轉移是否有不同的影響結果。我們將運用我們先前已成功建立的小鼠乳癌皮下腫瘤及器官(腦，肺，骨)腫瘤轉移模型，以及人類正常組織細胞(包括星狀細胞，肺泡細胞等)與癌細胞培養皿內共同培養的研究模式進行深入研究。 我們預期此一研究將建立全新的抑制腫瘤血管新生藥物合併化學治療在轉移性癌症使用的理論基礎根據，對於未來臨床運用將有深遠重要的影響。<br> Abstract: For decades, angiogenesis has been a potential treatment target for solid tumors. In monotherapy, antiangiogenic agents have demonstrated limited activity in most cancer types. The vasculature established in tumors is generally dysfunctional, exhibiting tortuous, dilated, and leaky. Elevated interstitial pressure, hypoxia, and acidosis resulted from the typical tumor microenvironment interfere with the delivery and the cytotoxic effects of chemotherapy (CT). Several studies have demonstrated that careful use of antiangiogenic therapy may cause the grossly abnormal structure and function of tumor blood vessels to return to a more normal state. According to a theory by Rakesh Jain, treatment with antiangiogenic agents may primarily improve CT efficacy by normalizing tumor vasculature, reducing tumor interstitial pressure, and correcting hypoxia and acidosis, thereby leading to more effective drug delivery and cytotoxic action. The strategy of adding anti-angiogenic therapy to CT has been evaluated in multiple cancer types. Although numerous studies have demonstrated the benefits of bevacizumab (Bev), an antivascular endothelial growth factor (anti-VEGF) antibody, overall survival has only improved in limited trials. The most salient example is that of metastatic breast cancer, for which the initial success of a clinical trial following a weekly CT schedule led to the approval of Bev by the U.S. Food and Drug Administration (FDA). However, when the magnitude of improvement of clinical efficacy could not be repeated in subsequent trials using tri-weekly CT schedules and administering Bev and CT on the same day, and no OS advantage was shown, the FDA revoked this approval. By considering the theory that antiangiogenic therapy inducing tumor vessel normalization thereby facilitating the delivery of chemotherapy into tumor may be the most crucial mechanism of synergism between CT and antiangiogenic therapy, we hypothesized that an optimal schedule and sequence between antiangiogenic therapy and CT is key to maximizing the efficacy of this combination. Our preliminary in vivo and clinical studies have strongly supported this hypothesis. In addition, other than an adjustment to the treatment sequence as a possible reason of improved treatment efficacy, our preliminary in vitro study demonstrated that co-culturing human stoma cells with cancer cells induced cancer cells resistant to CT, and that pretreatment with Bev could partially reverse this resistance. In this study, we plan to carefully re-assess and attempt to determine the optimal approach for combining antiangiogenic therapy with CT to treat solid tumors. Specific aims: 1. Determine an optimal schedule and timing for administering antiangiogenic therapy when combined with CT for the treatment of common solid tumors, focusing on the timing and duration of vascular normalization window. 2. Explore the additional mechanisms of the antiangiogenic therapy-induced chemosensitization effect in cancer cells, focusing on the interactions between cancer cells and normal tissue cells in a microenvironment after antiangiogenic therapy. The results of this study will be used to define an approach to maximize improvements in the clinical efficacy of CT by appropriately using antiangiogenic agents to treat solid tumors. The findings are crucial for the success of antiangiogenic therapy in the treatment of metastatic cancer.