In vivo efficacy of HSV-TK transcriptionally targeted to the tumour vasculature is augmented by combination with cytotoxic chemotherapy.
BACKGROUND
Retroviral vectors are suitable for targeting endothelial cells in the tumour neovasculature because of their intrinsic selectivity for proliferating cells. Previously, we inserted regulatory elements of the endothelial-specific prepro-endothelin-1 (ppET1) promoter in retroviral vectors to generate high-titre, replication-defective recombinant retroviruses that restricted gene expression to the vascular compartment of tumours.


METHODS
A retroviral vector was generated in which expression of herpes simplex virus thymidine kinase (HSV-TK) was transcriptionally restricted to endothelial cells, under the control of a hybrid ppET-1 LTR. Xenograft tumour models were used to determine the efficacy of targeting HSV-TK to the tumour vasculature. Subsequently, vascular-targeted gene therapy was combined with chemotherapeutic agents.


RESULTS
Breast or colorectal xenograft tumour growth was reduced and survival was increased in response to ganciclovir treatment. Treatment resulted in widespread vascular disruption and tumour cell apoptosis. In colorectal tumours, combination with irinotecan, a cytotoxic drug used to treat colorectal cancer, significantly increased survival compared to drug alone. No beneficial effect on survival was observed when combined with cisplatin, a cytotoxic drug not in clinical use for this tumour type. On the basis of their relative efficacies in vitro against tumour and endothelial cells, co-operativity with irinotecan likely derives from additionally targeting the peripheral tumour cells that survive the anti-vascular treatment.


CONCLUSIONS
We show that the ppET1-targeted vector is efficacious for therapeutic gene expression in vivo, validating a strategy targeted to tumour vasculature, and demonstrate that vascular targeting combined with appropriate chemotherapy is more effective than either therapy alone.
Mavria
Georgia
G
Section of Cell and Molecular Biology, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK. georgia.mavria@icr.ac.uk
Harrington
Kevin J
KJ
Marshall
Christopher J
CJ
Porter
Colin D
CD
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use; D001011:Aorta / Q000166:cytology; D002166:Camptothecin / Q000031:analogs & derivatives / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D042783:Endothelial Cells / Q000166:cytology / Q000502:physiology; D017930:Genes, Reporter; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000077146:Irinotecan; D009369:Neoplasms / Q000098:blood supply* / Q000188:drug therapy*; D012190:Retroviridae / Q000235:genetics / Q000378:metabolism; D018139:Simplexvirus / Q000201:enzymology*; D015996:Survival Rate; D013552:Swine; D013937:Thymidine Kinase / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D016896:Treatment Outcome
D000972:Antineoplastic Agents, Phytogenic; D000077146:Irinotecan; D013937:Thymidine Kinase; D002945:Cisplatin; D002166:Camptothecin