Oncolysis by viral replication and inhibition of angiogenesis by a replication-conditional herpes simplex virus that expresses mouse endostatin

John T. Mullen, James M. Donahue, Soundararajalu Chandrasekhar, Sam S. Yoon, Wenbiao Liu, Lee M. Ellis, Hideo Nakamura, Hideki Kasuya, Timothy M. Pawlik, Kenneth K. Tanabe

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)869-877
Number of pages9
JournalCancer
Volume101
Issue number4
DOIs
StatePublished - Aug 15 2004
Externally publishedYes

Keywords

  • Angiogenesis
  • Colon carcinoma
  • Endostatin
  • Herpes simplex virus 1
  • Oncolysis

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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