Oncolysis by viral replication and inhibition of angiogenesis by a replication-conditional herpes simplex virus that expresses mouse endostatin.
BACKGROUND
In preclinical models, infection of tumors by oncolytic strains of herpes simplex virus 1 (HSV-1) resulted in the destruction of tumor cells by viral replication and release of progeny virion that infected and destroyed adjacent tumor cells. However, complete tumor regression was rarely observed.


METHODS
To augment the antitumor effect of viral oncolysis, a replication conditional HSV-1 mutant (HSV-Endo) was constructed in which the murine endostatin gene was incorporated into the HSV-1 genome.


RESULTS
Replication of HSV-Endo effectively destroyed several colon carcinoma cell lines in vitro. Secretion of endostatin by HSV-Endo-infected HT29 human colon carcinoma cells was confirmed by Western blot analysis. The secreted endostatin was biologically active as assessed in a chick chorioallantoic membrane assay. Importantly, endostatin production at the site of viral replication did not inhibit viral replication. Direct injection of HSV-Endo into flank tumors caused tumor destruction, and some of the HSV-Endo-treated flank tumors completely sloughed. Immunohistochemical staining of the tumors revealed a decreased number of blood vessels in the HSV-Endo-treated group versus the control group.


CONCLUSIONS
The oncolytic HSV-1 mutant HSV-Endo provided a two-pronged therapy; namely, inhibition of angiogenesis and direct tumor cell destruction by viral replication.
Division of Surgical Oncology, Department of Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
John T
JT
Mullen
James M
JM
Donahue
Soundararajalu
S
Chandrasekhar
Sam S
SS
Yoon
Wenbiao
W
Liu
Lee M
LM
Ellis
Hideo
H
Nakamura
Hideki
H
Kasuya
Timothy M
TM
Pawlik
Kenneth K
KK
Tanabe
D000482:Allantois; D000818:Animals; D015153:Blotting, Western; D002645:Chickens; D002823:Chorion; D003110:Colonic Neoplasms / Q000473:pathology* / Q000821:virology*; D043169:Endostatins / Q000096:biosynthesis* / Q000235:genetics*; D005818:Genetic Engineering; D015316:Genetic Therapy / Q000379:methods*; D018259:Herpesvirus 1, Human / Q000235:genetics / Q000472:pathogenicity*; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D009389:Neovascularization, Pathologic; D014407:Tumor Cells, Cultured; D014779:Virus Replication
D043169:Endostatins