Use of adenoviral vectors to target chemotherapy to tumor vascular endothelial cells suppresses growth of breast cancer and melanoma.
To target chemotherapy to tumor vascular endothelial cells (TVECs), we created the AdTie2RprCDFib(knob-RGD+) vector by inserting into an AdEasy adenoviral vector (Ad) backbone: (i) the cytosine deaminase (CD) gene driven by the Tie2 receptor promoter (Tie2Rpr) into the E1 region of Ad; (ii) mutations that reduce binding of the fiber knob to the Coxsackie adenovirus receptor (CAR); and (iii) the RGD peptide into the H1 loop of fiber for binding to the alpha(V)beta(3) integrin receptors on TVECs. To reduce uptake of the AdTie2RprCDFib(knob-RGD+) by reticuloendothelial (RE) and liver cells, we intravenously (i.v.) injected Hetastarch and low-dose Ad (one million vector particles (VPs)) prior to i.v. injection of a therapeutic dose (one billion VPs) of the AdTie2RprCDFib(knob-RGD+) vector. This treatment induced regressions of N202 breast cancer and B16 melanoma without toxicity to normal tissues. We showed that the tumor regression was induced by infection of the TVECs and not by the infection of tumor cells by the AdTie2RprCDFib(knob-RGD+) vector.
Li
Pingchuan
P
Department of Genetic Therapy, Sidney Kimmel Cancer Center, San Diego, California, USA.
Liu
Yanzheng
Y
Maynard
Jonathan
J
Tang
Yucheng
Y
Deisseroth
Albert
A
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001943:Breast Neoplasms / Q000628:therapy*; D002460:Cell Line; D045744:Cell Line, Tumor; D043525:Cytosine Deaminase / Q000235:genetics / Q000502:physiology; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008545:Melanoma / Q000628:therapy*; D008546:Melanoma, Experimental / Q000628:therapy; D051379:Mice; D008819:Mice, Nude; D018613:Microscopy, Confocal; D011401:Promoter Regions, Genetic / Q000235:genetics; D042787:Receptor, TIE-2 / Q000235:genetics
D042787:Receptor, TIE-2; D043525:Cytosine Deaminase