抗血管新生療法在人類腫瘤的應用（1）

The Application of Anti-Angiogenesis Therapy in Human Cancer (PartⅠ)--Basic Science

腫瘤的生長與血管新生是密不可分的，當腫瘤長到1-2 mm大小以上時，即必須有血管新生開關啟動的現象才能維持腫瘤繼續生長。這種血管新生開關（angiogenic switch）是基於平衡假說（balance hypothesis），由血管新生促進因子與抑制因子兩者互相擷抗所控制。在不同種類腫瘤，血管新生開關啟動的時間點，可發生在轉變為惡性腫瘤之前、轉變為惡性腫瘤的同時、或轉變為惡性腫瘤之後發生。腫瘤血管的形成除了由已經存在的血管形成新血管稱為血管新生（angiogenesis）外，也有由循環性內皮前趨細胞即血管母細胞，由無血管狀態形成新的血管即脈管發生（vasculogenesis）。傳統的觀念上認為脈管發生只有在胚胎才會出現。然而，腫瘤血管的形成有血管新生與脈管發生兩種機轉，挑戰「脈管發生只出現在胚胎時期」的傳統觀念。同時，腫瘤血管的內壁並非由完全同質性的內皮細胞所構成。在某些侵襲性較高的腫瘤中如黑色素瘤及卵巢癌，腫瘤細胞本身會參與腫瘤血管內壁的形成、或由腫瘤細胞與內皮細胞互相鑲嵌形成腫瘤血管的內壁。由於腫瘤血管內皮細胞具有許多異質性和多變性、血管結構及功能異常、血流混亂、血管高通透性，及腫瘤內沒有淋巴引流等等特性，導致治療藥物的運輸困難。因此，動物試驗及臨床試驗仍遭遇許多的問題，目前並沒有得到很好的解決。抗血管新生療法（anti-angionenesis therapy）是一種新型對抗癌症的策略。藉著降低血管新生促進因子或增加血管新生抑制因子等方法，特異性地抑制腫瘤血管的內皮細胞，而造成腫瘤的萎縮，稱之為蟄伏療法（dormancy therapy）。使用抗血管新生療法於治療腫瘤，是以腫瘤血管的內皮細胞為攻擊標的，而非腫瘤細胞本身為攻擊標的，所以抗血管新生療法比起傳統化學療法是更具療效的潛力。近來的研究發現，當化學療法以長期而低劑量投與時，這種療程會比單一高劑量投與接續一段長時間休息的傳統療程對抑制血管內皮細胞有較好的效果。這種以長期而低劑量高頻率投與方式被稱為「節奏療程」（metronomic scheduling），投與劑量遠低於傳統最高容忍劑量（maximal tolerance dose）。其治療標的是腫瘤內相對較穩定的內皮細胞，在化學藥劑長期投與時可減少抗藥性的發生。目前抗血管新生療法的臨床前趨研究面臨亟待解決的問題包括；1.動物試驗中以皮下腫瘤為實驗模式，無法反應人類常見的腫瘤部位；2.抗血管新生療法的治療目標是使腫瘤維持蟄伏（tumor dormancy）狀態與傳統化學療法不一樣，所以需要的監視系統也與傳統化學療法不一樣；3.動物試驗無法區分生長快速與緩慢細胞；4.動物試驗也無法區分成熟與不成熟腫瘤血管；5.動物試驗期間過短，無法偵測長期使用抗血管新生療法的毒性反應；6.由動物試驗的結果無法直接推論到人體的反應；7.另外長期使用的藥物毒性反應及藥物投與的屏障也是要考慮的問題。

Accumulating literature reveals that tumor growth is closely related to angiogenesis. Tumor should turn on the 'anglogenic switch' in order to expand beyond the size of 1-2 mm,. The angiogenic switch is based on the balance hypothesis, which is governed by angiogenesis activators and inhibitors. The timing of angiogenic switch varies in different tumors; it can happen before, during or after the malignant trans-formation. Recent literature showed the tumor neovessels might come from angiogenesis, in which capillaries arise from the pre-existing capillaries; and vasculonesis, in which capillaries arise de novo from circulating endothelial progenitor cells, i.e., angioblasts. Traditionally, vasculogenesis was thought to happen only in the embryonic stage. However, tumor neovessel formation has been found to originate from both angiogenesis and vasculogenesis; this challenges the concept that vasculogenesis happens only in the embryonic stage. Meanwhile, it also has been shown that the inner linings of tumor vessels are not consisted Completely by homogenous endothelial cells. Instead, tumor cells themselves, as well as both tumor, cells and endothelial cells in mosaic pattern, participate in the formation formation of inner walls of tumor vessels in certain highly invasive types of tumors. Tumor neovessels have pleomorphic characteristics such as heterogeneity, versatility, highly permeability, multiple vascular markers, and turbulent blood flow with no lymphatic vessels within tumors. Their unique characteristics make therapeutic drug delivery difficult. Therefore, there are still many problems existing in animal experiments and clinical trials in anti-angiogenesis therapy. Anti-angiogenesis therapy is a new anti-cancer strategy by lowering the angiogenesis activators or increasing the angiogenesis inhibitors to attack tumor endothelial cells as its target, instead of tumor cells per se, with the final goal of tumor dormancy, called dormancy therapy. Thus, antiangiogenesis offers promising potential, when compared with traditional chemotherapy. Recent studies revealed 'metronomic scheduling' with long term, low dose continuous scheduling of chemotherapeutic agents has better results, as compared with traditional schedule with single high dose followed by long term recovery periods. The administration of metronomic scheduling is continuous, long term and low dosage which is much lower than the traditional maximal tolerance dose. The therapeutic targets are the stable endothelial cells, instead of highly variable tumor cells, with expected less drug resistance during long term administration. The present problems concerning preclinical study of anti-aogiogenesis therapy remains to be solved as follows. 1)The subcutaneous inoculations (xenograft) of tumor cells can represent spontaneous and orthototic human cancers; 2) The monitor systems should be different from those of traditional chemotherapy, because the aim of anti-angiogenesis therapy is tumor dormancy, which is different from traditional chemotherapy; 3) It is difficult to differentiate fast-growing cells from slow-growing cells in animal experiments; 4) It is difficult to differentiate mature and immature tumor vessels in animal experiments ;5) The study periods of present animal experiment designs are still not long enough to elucidate the toxicity of long term administration of anti-angiogenesis therapy; 6)It is difficult to implement the results of animal experiments directly to human responses; 7) Long term toxicity and drug delivery barriers are still the concerned problems.