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

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. Cancer 2004. © 2004 American Cancer Society.

Herpes simplex virus 1 (HSV-1) for cancer treatment

“…Oncolytic HSV-1 vectors have been used successfully to deliver immunoregulatory molecules, prodrug converting enzymes and angiogenesis inhibitors. 212 Synergism of antitumor effect was observed when oncolytic HSV-1 mutants were engineered to express cytokines. An elegant experiment done by Andreansky et al 213 clearly demonstrated that cytokine expression may be an important adjunct to oncolytic HSV-1 therapy.…”

Impact of novel oncolytic virus HF10 on cellular components of the tumor microenviroment in patients with recurrent breast cancer

“…[27][28][29] There are many attempts to engineer viruses to express antiangiogenic molecules. [30][31][32] Also obscuring the true effect of oncolytic herpes viruses on angiogenesis is the fact that all data have been generated in animal models rather than clinical investigation.…”

In vivo efficacy of systemic tumor targeting of a viral RNA vector with oncolytic properties using a bispecific adapter protein

“…Viral therapeutics can be tailored to attack genetic defects commonly found in tumor cells (2). Several oncolytic viruses (either native or genetically engineered), such as replication-competent adenovirus (3), herpes simplex virus (HSV) (4), and vesicular stomatitis virus (VSV) (5) carrying foreign genes have been reported to behave like 'armed' virus vectors in cancer treatment. The use of replication-competent viral vectors instead of traditional replication-defective viruses allows amplification of the potential therapeutic anti-tumor effects (6,7).…”