人類脂肪幹細胞載體傳送治療性反轉錄病毒應用於腦瘤治療

神經膠質瘤是腦癌當中最為惡性的一種腫瘤，即使進行大範圍的手術切除、化學治療及放射線治療都難以治癒。神經膠質瘤之所以難以治癒主因為此腫瘤細胞具有高度滲透性會侵襲入正常腦組織。近來在許多腦癌治療的研究中發現，幹細胞可以做為傳送治療分子的載體。因此，我們想利用脂肪幹細胞載體來傳送治療性反轉錄病毒到達腫瘤所在位置並且進行治療。在本研究中我們利用攜帶複製型反轉錄病毒 ACE-GFP的脂肪幹細胞來進行幹細胞於腫瘤的病毒傳播測試，由實驗結果可看到，由脂肪幹細胞釋放出的 ACE-GFP 可以感染U87人類神經膠瘤細胞，並且使 U87 表達出病毒傳送的GFP基因。透過細胞移動實驗，我們證實脂肪幹細胞對於 U87 具有趨向性。並且，在原位腫瘤的動物實驗中，我們也看到脂肪幹細胞能夠釋放 ACE-GFP 專一性地感染腫瘤，使 U87 表達病毒傳送的 GFP。接著利用脂肪幹細胞傳送帶有自殺基因的病毒（ACE-CD）進行毒殺實驗，於加入前藥 5-Fluorocytosine（5-FC）後，U87 的存活率明顯地下降。最後進行原位腫瘤的治療實驗，利用脂肪幹細胞傳送 ACE-CD 搭配 5-FC 治療後亦能有效延緩動物發病時間。期望未來可建立一個更具專一性的治療策略來治療腦瘤。

關鍵字

腦瘤；脂肪幹細胞；基因治療

並列摘要

Glioma accounts for the majority of primary malignant brain tumors and remains virtually incurable despite extensive surgical resection, radiotherapy, and chemotherapy. Glioma is difficult to treat because it has an exceptional infiltrative potential and proclivity to integrate into normal brain tissue. Recently, stem cells have been found offering much promise as delivery vehicles for brain tumor therapy. We hypothesized that human adipose-derived stem cells (hASCs) possess the ability to deliver therapeutic virus vectors to tumor sites. In this study, we examined the hypothesis in U87 by using hASCs infected with a replicating retrovirus vector (RRV) containing green fluorescent protein（GFP）. The result shows that GFP expressing RRV released from the hASCs could further infect glioma cells, achieving tumor-selective and persistent gene delivery to tumors. We have also tested the tumor-tropic migratory ability of hASCs and investigated the efficiency of hASCs to deliver RRV to glioma cells in vitro and in vivo. Next，We evaluated the therapeutic effects of hASCs-ACE-CD (cytosine deaminase) in MTT assay. Finally we also evaluated the therapeutic ability of hASCs-ACE-CD in an orthotopic mouse model of human glioma. We wish the use of hASCs as the vehicle for dispersing RRV may provide a viable strategy for delivering a therapeutic payload to disseminated glioma burdens.

並列關鍵字

glioma ； Adipose derived Stem Cells ； gene therapy

參考文獻

1 Surawicz, T. S., Davis, F., Freels, S., Laws, E. R., Jr. & Menck, H. R. Brain tumor survival: results from the National Cancer Data Base. Journal of neuro-oncology 40, 151-160 (1998).

2 Gurney, J. G. & Kadan-Lottick, N. Brain and other central nervous system tumors: rates, trends, and epidemiology. Current opinion in oncology 13, 160-166 (2001).

3 Lassman, A. B. & DeAngelis, L. M. Brain metastases. Neurologic clinics 21, 1-23, vii (2003).

4 Chang, E. L. & Lo, S. Diagnosis and management of central nervous system metastases from breast cancer. The oncologist 8, 398-410 (2003).

5 Weil, R. J., Palmieri, D. C., Bronder, J. L., Stark, A. M. & Steeg, P. S. Breast cancer metastasis to the central nervous system. The American journal of pathology 167, 913-920, doi:10.1016/S0002-9440(10)61180-7 (2005).

國際替代計量

人類脂肪幹細胞載體傳送治療性反轉錄病毒應用於腦瘤治療

未授權

主題瀏覽