Systemic administration of radiation-potentiated anti-angiogenic gene therapy against primary and metastatic cancer based on transcriptionally controlled HSV-TK.
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 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.
Hodish
Israel
I
Vascular Biogenics Ltd., Or-Yehuda, Israel.
Tal
Reshef
R
Shaish
Aviv
A
Varda-Bloom
Nira
N
Greenberger
Shoshana
S
Rauchwerger
Ariela
A
Breitbart
Eyal
E
Bangio
Livnat
L
Ben-Shushan
Dikla
D
Pfeffer
Raphael
R
Feder
Bela
B
Waitsman
Ana
A
Barshack
Iris
I
Goldberg
Iris
I
Mazaki-Tovi
Shaly
S
Peled
Michael
M
Harats
Dror
D
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003131:Combined Modality Therapy; D019332:Endothelin-1 / Q000235:genetics; D015774:Ganciclovir / Q000494:pharmacology*; D005786:Gene Expression Regulation; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000473:pathology / Q000628:therapy*; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000473:pathology / Q000628:therapy; D011401:Promoter Regions, Genetic / Q000235:genetics; D011498:Protein Precursors / Q000235:genetics; D011878:Radiotherapy; D018139:Simplexvirus / Q000201:enzymology; D016019:Survival Analysis; D013937:Thymidine Kinase / Q000235:genetics / Q000378:metabolism*; D047368:Tumor Burden / Q000187:drug effects / Q000528:radiation effects
D000998:Antiviral Agents; D019332:Endothelin-1; D011498:Protein Precursors; C093240:proendothelin 1; D013937:Thymidine Kinase; D015774:Ganciclovir