Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/20275
標題: 探討錸-188標記之賀癌平治療對於攝護腺癌細胞存活之影響
Inhibitory effects of Re-188 labeled Herceptin on prostate cancer cell survival: a possible radioimmunotherapy to prostate carcinoma
作者: 王心怡
Wang, Hsin-Yi
關鍵字: 賀癌平;Herceptin;攝護腺癌;錸;prostate cancer;Rhenium
出版社: 生命科學系所
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摘要: 
研究動機
男性特有的器官,攝護腺,在生長和分化上受到了男性荷爾蒙高度的調控。當轉變成癌症時,大於九成的攝護腺癌仍對於男性荷爾蒙有依賴性,因此可藉由抑制男性荷爾蒙的方式來控制攝護腺癌的生長,這就是所謂的荷爾蒙治療。但這種療法僅能減緩腫瘤的進展及轉移,但並無法像手術或放射治療一樣可以做為根除治療,因此多使用在晚期的攝護腺癌患者身上,或是作為手術或放射治療等的輔助治療。
雖然荷爾蒙治療對於攝護腺癌的控制效果非常顯著,但使用了一段時間之後,不免會產生抗藥性,這時可用的治療方式有限,患者的預後也不理想。為了改善這個困境,本研究就想利用攝護腺癌腫瘤表面上HER2 (Human Epidermal Growth Factor Receptor 2,人類上皮生長因子第二型接受器)的表現量,會在荷爾蒙治療後明顯上升的現象,來發展一個新的療法。
Trastuzumab (商品名:賀癌平,Herceptin)是用來對抗HER2高表現型乳癌的藥品。本研究利用這個單株抗體對於HER2的高親和性,來攜帶治療性的放射性同位素(錸-188)到HER2高表現腫瘤處進行治療,這個新的核醫藥物就是本研究的標的:Re-188 Herceptin (Re-H)。以下將會分別以體外及體內的方式,評估這個藥物對於HER2高表現的攝護腺癌的治療效果。

研究方法與設計
本研究所使用高HER2表現的攝護腺癌細胞株為DU145,在使用Re-188 Herceptin治療之後,評估細胞的生長情形,凋亡程度及相關蛋白的變化。除了Re-188 Herceptin這個標的藥物之外,也使用了未標記同位素的Herceptin,未標記Herceptin的同位素Re-188以及生理鹽水(PBS)分別治療,作為對照組。在確定了藥物在體外的表現之後,則將DU145的攝護腺癌細胞株打在小鼠的皮下,待其長成腫瘤之後,再以前述藥物加以治療,除了觀察腫瘤生長及相關蛋白的變化之外,也評估了此藥物在體內的分布情形。

研究結果
在體外研究中,攝護腺癌細胞株DU145的生長受到Re-H及Re-188抑制,此抑制隨著給予的劑量及治療後的時間而增加,而對照組的Herceptin 及PBS則無此現象。細胞凋亡的現象也在Re-H治療後出現,在其他的對照組則不明顯。鼠體內的藥物分佈顯示Re-H果然因Herceptin的特異性而聚集在小鼠皮下的腫瘤。治療後的腫瘤生長受到抑制,凋亡相關蛋白出現相對應的變化,甚至連藉由活化Cdk5來調控腫瘤細胞存活及侵襲性的p35也出現了明顯的下降。

討論建議
本研究顯示Re-188 Herceptin可有效抑制高HER2表現的攝護腺癌細胞株DU145的生長,這是單純使用Re-188 或Herceptin所達不到的。Re-188 Herceptin這個新的核醫藥物可望日後可以應用在具高HER2表現的攝護腺癌患者身上。

Background:
Advanced or metastatic prostate cancers tend to turn into castration-resistant cancers after hormonal therapy. Most of these cases are characterized by elevated HER2 expression and have poor prognosis. Herceptin (Trastuzumab), a humanized anti-HER2 monoclonal antibody, is widely used for the treatment of patients with HER2-overexpressing breast cancer. However, the application of Herceptin in prostate cancer patients is still controversial. In order to understand whether radioimmunotherapeutic strategy is more effective than immunotherapy by attacking HER2 alone, we labeled the Rhenium-188, a beta emitter, onto Herceptin to evaluate its radioimmunotherapeutic effect on prostate cancer with elevated HER2 expression in vitro and in vivo compared with immunotherapy with Herceptin alone and radiotherapy with Re-188 alone.

Methods:
DU145, an androgen receptor negative prostate cancer cell line with elevated HER2 expression, was used to evaluate the therapeutic effect of the Herceptin labeled with Rhenium-188 (Re-188), a beta emitter. Its effect is evaluated in vitro on cell growth, extent of apoptosis, protein levels as well as in vivo on bio-distribution, tumor growth, apoptosis and protein levels.

Results:
The proliferation of DU145 cells was inhibited after treated with the Re-188 Herceptin (Re-H) in dose- and time-dependent manners but not in the control groups treated with PBS (phosphate buffered saline) and Herceptin alone. The proliferate inhibition and apoptosis were induced after Re-H treatment. The in vivo xenograft study revealed tissue-specific bio-distribution of Re-188 Herceptin, which results in significant decrease of tumor growth and correlated changes of apoptosis-related proteins. Moreover, the level of p35 protein, which responds for cancer cell survival and invasion by activating Cdk5, dramatically decreased after Re-188 Herceptin treatment.

Conclusion:
Our data indicate that Re-188 labeled Herceptin effectively inhibited the growth of DU145 cells compared to the Herceptin- and Re-188-treated cohorts. This implies that targeting Her2 by both radio- and immuno- therapy might be a potential strategy for treating patients with castration-resistant prostate cancer.
URI: http://hdl.handle.net/11455/20275
其他識別: U0005-1007201313384500
Appears in Collections:生命科學系所

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