腫瘤的血管生成和轉移對於組織侵犯是一種相當重要的因素，對於癌症的治療成為一個引人注目的目標；Melittin是從西方蜜蜂的毒素中所分離出來的一種雙極性peptide，已經為人所知它具有很強的抗發炎和抗微生物的作用。首先；我們測試melittin在具有高度侵犯力的鼷鼠黑色素瘤細胞B16F10的體外試驗作用，Melittin對於B16F10細胞膜滲透性作用的調查乃藉由測試從細胞漏出的大分子和生化數值，我們發現melittin誘導葡萄糖(glucose)、鉀離子(K+)、磷(phosphorus)、乳酸脫氫(LDH)和胺基轉移(GOT and GPT)的釋放以及鈣離子的流入，而melittin對於細胞內的鈉離子(Na+)、氯離子(Cl-)、鎂離子(Mg2+)、澱粉(amylase)和肌酸激(creatine kinase)則無顯著影響。 Melittin的功能活性分析藉由監測細胞內鈣離子的流入以及對於BAPTA/AM，EGTA和TG的反應，當B16F10細胞受到melittin的刺激時會造成相當的鈣離子流入，B16F10細胞預先處理了BAPTA/AM，EGTA和TG會延遲melittin對細胞的裂解時間；在高度的劑量下，melittin 會造成B16F10細胞染色體去氧核糖核酸成碎片，細胞的凋亡和裂解。Melittin也被用來評估抑制B16F10細胞的侵犯力，我們結合了Matrigel outgrowth 和Boyden chamber分析的原理，利用侵犯抑制劑的三步驟監視方法，加入melittin 0.3或1 μM與控制組作比較，腫瘤細胞無法侵入到matrigel底部分別是控制組的2.4和2.3倍，而腫瘤細胞已經侵入到matrigel底部分別是控制組的80.67 ±1.54 % 和 72.67 ±1.33 %。
其次，我們測試melittin在B16F10細胞的體內試驗作用，我們測試melittin對於鼷鼠黑色素瘤細胞B16F10在鼷鼠肺部的轉移抑制作用，不同的melittin 給予方式(腹腔注射)發現非常有效地抑制黑色素瘤細胞B16F10在鼷鼠肺部的轉移，可藉由觀察肺部內腫瘤小結節數目的減少(14-86%)而知道，同樣的情形在皮下和腹腔的腫瘤生成分析中也可發現melittin減少了腫瘤小結節在鼷鼠皮下和腹腔的擴散和增生。為了研究melittin對於B16F10腫瘤細胞所誘導的血管生成作用，我們沿著鼷鼠腹部中線植入含有B16F10細胞的matrigel到鼷鼠皮下組織，接種後第九天測量matrigel所含的血紅素濃度，結果顯示接種後連續五天給予鼷鼠腹腔注射melittin 0.5 μg/g會降低matrigel內的血管生成能力。另外，在肺部、皮下和腹腔的腫瘤生成分析中，給予melittin治療會使含有轉移性腫瘤的鼷鼠其存活期增長。因為melittin本身具有毒性，所以測試melittin在鼷鼠體內的溶血活性和急毒性，結果顯示給予鼷鼠melittin 0.6 μg/g(實驗的最高劑量)有抑制腫瘤轉移和血管生成的作用，與沒有給予melittin的鼷鼠比較，此劑量亦不會影響鼷鼠體重、紅血球裂解和血清的生化值。
由以上結果推論，我們証實melittin它具有抑制腫瘤細胞的侵犯和血管生成的能力足以成為引人注意的抗癌藥物，結合更進一步地研究和傳統的細胞毒殺化學治療藥劑，或許Melittin可以証明能更有效地控制癌症的過程。

Tissue invasion is an important determinant of angiogenesis and metastasis of tumors and constitutes an attractive target for cancer therapy. Melittin, an amphiphilic peptide isolated from honeybee Apis mellifera, is known to provide strong anti-inflammatory and antimicrobial effect. First, we tested the effect of melittin on the highly invasive murine melanoma B16F10 cells in vitro. Effect of melittin on membrane permeability of B16F10 cells was investigated by measuring the leakage of macromolecules and biochemical data. We found that melittin induced the release of glucose, K+, phosphorus, LDH, GOT, GPT, and increased Ca2+ influx. No significant influence of melittin on the contents of Na+, Cl-, Mg2+, amylase and creatine kinase. Functional activity assays of melittin was conducted by monitoring intracellular calcium fluxes in response to BAPTA/AM, EGTA and TG. B16F10 cells exhibit robust intracellular Ca2+ fluxes when stimulated with melittin. Pretreatment with BAPTA/AM, EGTA and TG of B16F10 cells delayed lytic time by melittin. In the high dose, melittin cause DNA fragmented, cell apoptosis and lysis. Melittin was estimated in inhibitive effect of B16F10 cell invasion. We have combined the principles of the Matrigel outgrowth and the Boyden chamber assays in a three-step screen for invasion inhibitors. Addition of melittin 0.3 or 1 μM, cells that failed to invade to Matrigel were 2.4 and 2.3 fold respectively compared with control, and cell invaded to Matrigel were 80.67 ±1.54 % and 72.67 ±1.33 % respectively compared with control.
Second , we tested the effect of melittin on the B16F10 cells in vivo. We examined the effect of melittin on the inhibition of lung metastasis induced by murine melanoma cells B16F10 in mice. Various administrations (i.p.) of melittin were found effectively to inhibit the lung metastasis as seen by the reduction in the number of lung tumor nodules (14-86%). Similar circumstances were found that melittin decreased dissemination and proliferation of tumor nodules in subcutaneous and abdominal tumorigenesis assay. To study the effect of melittin on B16F10 tumor-induced angiogenesis, we implanted Matrigel with B16F10 cells to abdominal s.c. tissue of mice along the peritoneal midline. Hemoglobin content of matrigel was measured after 9 days inoculation. The results obtained showed that the mice treated with melittin 0.5 μg/g (i.p. once everyday for 5 consecutive days) decreased angiogenic potential of Matrigel. In addition, life span of metastatic tumor bearing mice treated with melittin were also found to be increased in all models of lung, subcutaneous and abdominal tumorigenesis assay. Because melittin itself possessed toxicity, so we tested hemolytic activity and acute toxicity of melittin in vivo. It reveals give dose mice were administrated melittin 0.6 μg/g effect in inhibiting the metastasis and angiogenesis but had no significant influence on body weight, erythrocyte lysis and biochemical data of serum compared with the control mice without melittin administration.
In conclusion, we have demonstrated that melittin that has the potential for inhibiting tumor cell invasion and angiogenesis is attractive candidates as an anticancer agent. It merits for further study that in combination with the conventional cytotoxic chemotherapy agents, it may prove to be efficacious in controlling cancer progression.

目錄
Abbreviations……………………………………………………………1
中文摘要………………………………………………………………...2
Abstract…………………………………………………………………..6
Introduction……………………………………………………………..10
Materials and Methods………………………………………………….22
Results…………………………………………………………………..34
Discussion………………………………………………………………47
Tables……………………………………………………………………56
Figures…………………………………………………………………..65
References……………………………………………………………..109

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