抗血管新生療法在人類腫瘤的應用（2）

The Application of Anti-Angiogenesis Therapy in Human Cancer (Part Ⅱ)--Clinical Medicine

抗血管新生療法（anti-angiogenesis therapy）是一種新型對抗癌症的策略。使用抗血管新生療法根據的理論基礎為以腫瘤血管的內皮細胞為治療藥物的攻擊標的；腫瘤血管的內皮細胞基因比較穩定、同質性高、而且突變率低；投與的藥物可以直接接觸內皮細胞，減少投與藥物屏障，因此增加有效投與藥物的能力及減少藥物副作用；以截斷供應腫瘤氧氣養分的血管為目標；以減小腫瘤的體積大小（tumor burden）為目的，與傳統化學療法以根除腫瘤的目標不同。抗血管新生療法用於臨床治療腫瘤的策略包括；抑制血管新生促進因子的配合基及其受體、增加內生性或合成性血管新生抑制因子、直接作用在腫瘤血管內壁、提供基質金屬蛋白瓷抑制劑（matrix metallo-proteinase inhibitor）等。經由對於血管新生以及腫瘤的分子生物學特質的研究，進一步了解抗血管新生療法可以經由抑制腫瘤的血管新生，間接延緩侵襲前腫瘤變成惡性腫瘤，抑制腫瘤的生長，達到治療原發性腫瘤及轉移性腫瘤的目的。近年來抗血管新生療法的進展，目前已有超過75種抗血管新生藥物由前臨床試驗進入臨床試驗，其中12種已進入第三相臨床試驗。其中，avastin、marimastat、interferon、thalidomide等藥物更是有較明顯的潛力。然而，目前臨床試驗仍有一些困難，包括由第一相臨床試驗往後續試驗的劑量調整決定適當生物劑量（optimal biologic dose）、治療療程（scheduling）的決定、如何決定評估試驗的生物終點（biologic end points）、適當臨床病患的選擇、如何結合抗血管新生藥物與其他化學療法或放射療法、以及抗血管新生藥物個別化（angiogenic profiling）等問題、將來發展的可能方向包括：合併數種抑制因子療法：將抗血管新生療法與傳統化學療法合併使用；將抗血管新生療法與放射療法合併使用；以特異的腫瘤血管標記為治療目標，直接阻斷供給腫瘤的血管：以血管及造血幹細胞為治療目標；對腫瘤血管內壁成分有進一步了解；同時尋找更新的影像或生物替代標記（surrogate markers）來監測腫瘤血管的功能；提高腫瘤內的氧分壓來提高投藥效果也都是可能的方向；因個人基因背景不同去調配治療藥物以符合個人不同的需要。由目前的臨床試驗顯示，抗血管新生療法治療人類癌症，提供在不同時期癌發生過程中對抗癌症非常有希望的策略。然而抗血管新生療法在進入臨床試驗的過程時，仍然還有許多的問題值得科學界、醫學界更進一步的研究探討。

Anti-angiogenesis therapy is a new anti-cancer strategy based on the fact, that tunior growth is angiogenesis-dependent. The rationals of anti-angiognesis are the following: the therapeutic target is tumor endothelial cells which are more genetically stable, more homogeneous, and with lower mutation rate; the anti-angiogenesis drugs can contact endothelial cells directly, with higher potency and lower drug barriers and side effects; the aim of anti-angiogenesis therapy is to block the oxygen and nutrition supply from vessels, instead of killing tumor cells perse; the aim of anti-angiogenesis is to reduce tumor size instead of eradicate tumor, which are different from traditional chemotherapy. The strategies of anti-angiogenesis include decreasing angiogenesis activators and their receptors; increasing endogenous or synthetic angiogenesis inhibitors; direct affecting inner linings of tumor vessels; providing matrix metallo-proteinasa inhibitors, etc. Through the research of angiogenesis and understanding of molecular biology of tumors, we can elucidate the potentials of anti-angiogenesis in delaying the progression of precancerous lesions to invasive cancers, inhibiting tumor growth by inhibiting tumor angiogenesis with the final goals of curing primary and metastatic tumors. There were more than 75 anti-angiogenesis drugs which have entered the clinical trial from pre-clinical trials. Among them, 12 drugs e.g, avastin, marimastat, interferon, thalidomide, etc have already entered phase 3 clinical trials and shown obvious therapeutic potential. However, there are still some difficulties remained unsolved, e,g, the adjustment of optimal biologic dose, the determination of therapeutic scheduling and biologic end points, the selection of appropriate patients, the combination of anti-angiogenesis with other modalities such as chemotherapy and/or radiotherapy, individual angiogenic profiling, etc. The future directions for anti-angiogenesis therapy may include; combining several anti-angiogenesis agents; combiningantanti-angiogenesis and traditional chemotherapy, and/or radiotherapy; the use of specific vessel markers as direct vessel targets to block the supplying vessels; the use of hematopoietic stem cells as therapeutic targets; the sophisticated understanding of inner linings of tumor vessels; the search of newer image systems or surrogate markers to monitor tumor vessel functions; the increase of oxygen tension in order to increase drug efficacy; the adjustment of pharmaceutical drugs according to individual genetic background. From present studies, anti-angiogenesis offers a new highlight of anti-cancer therapy in different stages of cancer. However, there are still some problems that remain to be solved during the transition of clinical trials.