Endothelial cell vehicles for delivery of cytotoxic genes as a gene therapy approach for carcinoma of the ovary.
Human umbilical vein endothelial cells (HUVECs) were evaluated for utility as a vector to achieve a bystander effect and killing of ovarian carcinoma cell lines. After demonstrating that HUVECs could be transduced with the reporter gene LacZ encoded by an adenoviral vector, appropriate cell killing of the AdCMVHSV-TK-transduced HUVECs was exhibited after treatment with 20 microM ganciclovir. Mixing experiments were then performed to determine whether the transduced HUVECs would demonstrate a bystander effect with the ovarian cancer cell lines. When 50% AdCMVHSV-TK-transduced HUVECs were mixed with untransduced ovarian cancer cells, > 70% of all cells were killed. Finally, s.c. and i.p. injections of herpes simplex-thymidine kinase-expressing HUVECs and SKOV3ip1 tumor cells were performed to evaluate the effects of HUVECs in in vivo models. These studies showed a decrease in tumor growth s.c. as well as a statistically significant survival prolongation (P < 0.05) in the i.p. model. These findings suggest that endothelial cells may be used as a vehicle for the delivery of cytotoxicity (bystander effect) in molecular chemotherapy.
Rancourt
C
C
Gene Therapy Program, Comprehensive Cancer Center, Birmingham, Alabama, USA.
Robertson
M W
MW
Wang
M
M
Goldman
C K
CK
Kelly
J F
JF
Alvarez
R D
RD
Siegal
G P
GP
Curiel
D T
DT
D000818:Animals; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D005260:Female; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D010051:Ovarian Neoplasms / Q000628:therapy*; D018139:Simplexvirus / Q000201:enzymology; D013937:Thymidine Kinase / Q000096:biosynthesis / Q000235:genetics; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured
D013937:Thymidine Kinase