In vivo murine tumor gene delivery and expression by systemic recombinant vaccinia virus encoding interleukin-1beta.
OBJECTIVE
This study investigates the feasibility of systemic gene delivery in a tumor-bearing host using a vaccinia virus-based in vivo gene delivery and expression system.


METHODS
A recombinant vaccinia virus encoding human interleukin-1beta (hIL-1beta) was constructed with a strong synthetic vaccinia virus late promoter driving hIL-1beta gene expression. C57BL/6 mice bearing established subcutaneous pancreatic tumors were injected intravenously in a blinded, randomized fashion with different doses of either the recombinant vaccinia virus(vMJ601hIL-Ibeta), control vaccinia (wild-type or TK-deficient), or saline. Toxicity was assessed, serial tumor sizes were measured, and viral titers and the amount of hIL-1beta in tumor, liver, and spleen were determined.


RESULTS
High viral titers (10(6) PFU/g) were detected in tumors for all three viruses on postinjection day 3, and tumor viral titers persisted at high levels until day 9. In contrast, viral titers were initially 104-fold lower in nontumor tissues and decreased to undetectable levels by day 9. vMJ60hIL-1beta was rapidly cleared from liver and spleen by day 3 (titer levels < 100 PFU/g), while tumor titer levels persisted at 8.5 x 10(6) PFU/g. hIL-1beta was measurable in three of three tumors from vMJ601hIL-1beta treated mice on postinjection day 3, one of three on day 6, and one of three on day 9; no hIL-1beta was detected in any other tumors or normal tissues. Wild-type vaccinia had no antitumor effects. Treatment with two different doses of vMJ601hIL-1beta resulted in a consistent and significant decrease in tumor size in repeatable experiments as compared to controls. Histologic analysis revealed tumor cell necrosis with a surrounding neutrophil infiltrate in the vMJ601hIL-1beta treated tumor.


CONCLUSIONS
These data show that recombinant vaccinia virus encoding hIL-1beta given intravenously preferentially localizes and amplifies in tumor tissue, is rapidly cleared from liver and spleen, produces measurable hIL-1beta in tumor but not normal tissues, and inhibits growth of established solid tumors in mice. Recombinant vaccinia virus encoding therapeutic genes may be a practical, efficient vehicle for direct in vivo gene transfer and expression in the treatment of cancer.
Peplinski
G R
GR
Department of Surgery, Washington University School of Medicine, St. Louis, Missouri 63110-1093, USA.
Tsung
A K
AK
Casey
M J
MJ
Meko
J B
JB
Fredrickson
T N
TN
Buller
R M
RM
Norton
J A
JA
D000818:Animals; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D007150:Immunohistochemistry; D007375:Interleukin-1 / Q000032:analysis / Q000235:genetics*; D008099:Liver / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000473:pathology / Q000628:therapy* / Q000821:virology; D010190:Pancreatic Neoplasms / Q000473:pathology / Q000628:therapy* / Q000821:virology; D011994:Recombinant Proteins; D013154:Spleen / Q000821:virology; D014616:Vaccinia virus
D007375:Interleukin-1; D011994:Recombinant Proteins