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
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
收藏
页码:435 / 443
页数:9
相关论文
共 28 条
[1]   DEVELOPMENT OF ANTITUMOR IMMUNITY FOLLOWING THYMIDINE KINASE-MEDIATED KILLING OF EXPERIMENTAL BRAIN-TUMORS [J].
BARBA, D ;
HARDIN, J ;
SADELAIN, M ;
GAGE, FH .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1994, 91 (10) :4348-4352
[2]   Gene therapy for SCID - a complication after remarkable progress [J].
Buckley, RH .
LANCET, 2002, 360 (9341) :1185-1186
[3]   A phase I/II trial of rAd/p53 (SCH 58500) gene replacement in recurrent ovarian cancer [J].
Buller, RE ;
Runnebaum, IB ;
Karlan, BY ;
Horowitz, JA ;
Shahin, M ;
Buekers, T ;
Petrauskas, S ;
Kreienberg, R ;
Slamon, D ;
Pegram, M .
CANCER GENE THERAPY, 2002, 9 (07) :553-566
[4]   Angiogenesis in cancer and other diseases [J].
Carmeliet, P ;
Jain, RK .
NATURE, 2000, 407 (6801) :249-257
[5]   Enhanced therapeutic effect of HSV-tk plus GCV gene therapy and ionizing radiation for prostate cancer [J].
Chhikara, M ;
Huang, HX ;
Vlachaki, MT ;
Zhu, XH ;
Teh, B ;
Chiu, KJ ;
Woo, S ;
Berner, B ;
Smith, EO ;
Oberg, KC ;
Aguilar, LK ;
Thompson, TC ;
Butler, EB ;
Aguilar-Cordova, E .
MOLECULAR THERAPY, 2001, 3 (04) :536-542
[6]   In vivo targeting of tumor endothelial cells by systemic delivery of lentiviral vectors [J].
De Palma, M ;
Venneri, MA ;
Naldini, L .
HUMAN GENE THERAPY, 2003, 14 (12) :1193-1206
[7]   Radiation enhances adenoviral gene therapy in pancreatic cancer via activation of cytomegalovirus promoter and increased adenovirus uptake [J].
Egami, Takuya ;
Huchida, Kenoki ;
Mizumoto, Kazuhiro ;
Onimaru, Manabu ;
Toma, Hiroki ;
Nishio, Shoko ;
Nagai, Eishi ;
Matsumoto, Kunio ;
Nakamura, Toshikazu ;
Tanaka, Masao .
CLINICAL CANCER RESEARCH, 2008, 14 (06) :1859-1867
[8]   Expression of Coxsackie adenovirus receptor and alphav-integrin does not correlate with adenovector targeting in vivo indicating anatomical vector barriers [J].
Fechner, H ;
Haack, A ;
Wang, H ;
Wang, X ;
Eizema, K ;
Pauschinger, M ;
Schoemaker, RG ;
van Veghel, R ;
Houtsmuller, AB ;
Schultheiss, HP ;
Lamers, JMJ ;
Poller, W .
GENE THERAPY, 1999, 6 (09) :1520-1535
[9]   Fundamental concepts of the angiogenic process [J].
Folkman, J .
CURRENT MOLECULAR MEDICINE, 2003, 3 (07) :643-651
[10]   Tumor response to radiotherapy regulated by endothelial cell apoptosis [J].
Garcia-Barros, M ;
Paris, F ;
Cordon-Cardo, C ;
Lyden, D ;
Rafii, S ;
Haimovitz-Friedman, A ;
Fuks, Z ;
Kolesnick, R .
SCIENCE, 2003, 300 (5622) :1155-1159