Systemic administration of radiation-potentiated anti-angiogenic gene therapy against primary and metastatic cancer based on transcriptionally controlled HSV-TK

被引：12

作者：

Hodish, Israel ^{[1
,2
]}

Tal, Reshef ^{[1
,2
]}

Shaish, Aviv ^{[1
,2
]}

Varda-Bloom, Nira ^{[1
,2
]}

Greenberger, Shoshana ^{[1
,2
]}

Rauchwerger, Ariela ^{[3
]}

Breitbart, Eyal ^{[1
]}

Bangio, Livnat ^{[1
]}

Ben-Shushan, Dikla ^{[2
]}

Pfeffer, Raphael ^{[4
]}

Feder, Bela ^{[5
]}

Waitsman, Ana ^{[5
]}

Barshack, Iris ^{[1
,6
]}

Goldberg, Iris ^{[6
]}

Mazaki-Tovi, Shaly ^{[7
]}

Peled, Michael ^{[1
,2
]}

Harats, Dror ^{[1
,2
]}

机构：

[1] Vasc Biogen Ltd, IL-60376 Or Yehuda, Israel

[2] Tel Aviv Univ, Tel Hashomer & Sackler Sch Med, Sheba Med Ctr, Bert W Strassburger Lipid Ctr, IL-69978 Tel Aviv, Israel

[3] Chaim Sheba Med Ctr, Internal Med Dept C, IL-52621 Tel Hashomer, Israel

[4] Chaim Sheba Med Ctr, Inst Oncol, IL-52621 Tel Hashomer, Israel

[5] Chaim Sheba Med Ctr, Dept Geriatr, IL-52621 Tel Hashomer, Israel

[6] Chaim Sheba Med Ctr, Inst Pathol, IL-52621 Tel Hashomer, Israel

[7] Chaim Sheba Med Ctr, Dept Obstet & Gynecol, IL-52621 Tel Hashomer, Israel

来源：

CANCER BIOLOGY & THERAPY | 2009年 / 8卷 / 05期

关键词：

endothelium; radiotherapy; adenovirus; promoter; gene therapy; angiogenesis; thymidine kinase; IN-VIVO; THYMIDINE KINASE; IONIZING-RADIATION; TUMOR ANGIOGENESIS; ENDOTHELIAL-CELLS; HUMAN ENDOSTATIN; DELIVERY; EXPRESSION; VECTORS; INHIBITION;

D O I：

10.4161/cbt.8.5.7589

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Transcription-targeted gene delivery directed against angiogenic endothelial cells is a new approach against advanced cancer. Moreover, the herpes simplex virus-thymidine kinase (HSV-TK) gene coupled with low dose radiotherapy is an efficient and externally controlled cytotoxic system. We have previously demonstrated enhanced endothelial-specific cell expression and killing using the modified murine pre-proendothelin-1 promoter (PPE1-3x) to direct adenoviral expression of a pro-apoptotic gene. The purpose of this study was to create an externally potentiated systemic anti-antiangiogenic gene delivery system based on an adenoviral vector expressing HSV-TK under the regulation of PPE1-3X promoter combined with radiotherapy for eradicating metastatic cancer. Ad-PPE1-3x-TK induced endothelial-specific cell killing in-vitro upon introduction of the prodrug ganciclovir (GCV). BALB/c mice bearing a primary CT-26 colon carcinoma tumor showed tumor growth suppression and diminished tumor angiogenesis when the vector was administered intravenously, activated with GCV and potentiated with a single sub-therapeutic and non-toxic radiation dose. Moreover, intravenous administration of the vector, activated with GCV and potentiated with chest aimed radiation, to C57BL/6 mice bearing Lewis lung carcinoma metastases resulted in prolongation of mice survival. PPE1-3x-regulated HSV-TK expression was detected only in lung metastases in contrast to CMV-regulated expression. This novel system may benefit patients with metastatic disease.

引用

页码：435 / 443

页数：9

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