Systemic administration of a matrix-targeted retroviral vector is efficacious for cancer gene therapy in mice.
Targeting cytocidal vectors to tumors and associated vasculature in vivo is a long-standing goal of human gene therapy. In the present study, we demonstrated that intravenous infusion of a matrix (i.e., collagen)-targeted retroviral vector provided efficacious gene delivery of a cytocidal mutant cyclin G1 construct (designated Mx-dnG1) in human cancer xenografts in nude mice. A nontargeted CAE-dnG1 vector (p = 0.014), a control matrix-targeted vector bearing a marker gene (Mx-nBg; p = 0.004), and PBS served as controls (p = 0.001). Enhanced vector penetration and transduction of tumor nodules (35.7 +/- 1.4%, mean +/- SD) correlated with therapeutic efficacy without associated toxicity. Kaplan-Meier survival studies were conducted in mice treated with PBS placebo, the nontargeted CAE-dnG1 vector, and the matrix-targeted Mx-dnG1 vector. Using the Tarone log-rank test, the overall p value for comparing all three groups simultaneously was 0.003, with a trend that was significant to a level of 0.004, indicating that the probability of long-term control of tumor growth was significantly greater with the matrix-targeted Mx-dnG1 vector than with the nontargeted CAE-dnG1 vector or PBS placebo. The present study demonstrates that a matrix-targeted retroviral vector deployed by peripheral vein injection (1) accumulated in angiogenic tumor vasculature within 1 hr, (2) transduced tumor cells with high-level efficiency, and (3) enhanced therapeutic gene delivery and long-term efficacy without eliciting appreciable toxicity.
Gordon
E M
EM
Gene Therapy Laboratories, Division of Colon and Rectal Surgery and Department of Pediatrics, Keck School of Medicine of the University of Southern California, Los Angeles, CA 90033, USA. emgordon@genome2.hsc.usc.edu
Chen
Z H
ZH
Liu
L
L
Whitley
M
M
Liu
L
L
Wei
D
D
Groshen
S
S
Hinton
D R
DR
Anderson
W F
WF
Beart
R W
RW
Hall
F L
FL
D000818:Animals; D003094:Collagen / Q000235:genetics* / Q000378:metabolism; D056746:Cyclin G; D056766:Cyclin G1; D016213:Cyclins / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D020287:In Situ Nick-End Labeling; D007262:Infusions, Intravenous; D051379:Mice; D008819:Mice, Nude; D012190:Retroviridae / Q000235:genetics*; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D014183:Transplantation, Heterologous; D001616:beta-Galactosidase / Q000378:metabolism
C534702:CCNG1 protein, human; C534703:Ccng1 protein, mouse; D056746:Cyclin G; D056766:Cyclin G1; D016213:Cyclins; D003094:Collagen; D001616:beta-Galactosidase