Angiogenesis inhibition by an oncolytic herpes virus expressing interleukin 12 Journal Article
| Authors: | Wong, R. J.; Chan, M. K.; Yu, Z.; Ghossein, R. A.; Ngai, I.; Adusumilli, P. S.; Stiles, B. M.; Shah, J. P.; Singh, B.; Fong, Y. |
| Article Title: | Angiogenesis inhibition by an oncolytic herpes virus expressing interleukin 12 |
| Abstract: | Purpose: Oncolytic herpes simplex viruses (HSVs) may have significant antitumor effects resulting from the direct lysis of cancer cells. HSVs may also be used to express inserted transgenes to exploit additional therapeutic strategies. The ability of an interleukin (IL)-12-expressing HSV to treat squamous cell carcinoma (SCC) by inhibition of tumor angiogenesis is investigated in this study. Experimental Design: A replication-competent, attenuated, oncolytic HSV carrying the murine IL-12 gene (NV1042), its non-cytokine-carrying analog (NV1023), or saline was used to treat established murine SCC flank tumors by intratumoral injection. The expression of secondary antiangiogenic mediators was measured. Angiogenesis inhibition was assessed by in vivo Matrigel plug assays, flank tumor subdermal vascularity, and in vitro endothelial cell tubule formation assay. Results: Intratumoral injections of NV1042 (2 × 107 plaque-forming units) into murine SCC VII flank tumors resulted in smaller tumor volumes as compared with NV1023 or saline. IL-12 and IFN-γ expression in tumors was 440 and 2.2 pg/mg, respectively, at 24 h after NV1042 injection, but both IL-12 and IFN-γ were undetectable (<0.2 pg/mg) after NV1023 or saline injections. Expression of two antiangiogenesis mediators, monokine induced by IFN-γ and IFN-inducible protein 10, was elevated after NV1042 treatment. Matrigel plug assays of NV1042-transfected SCC VII tumor cells demonstrated significantly decreased hemoglobin content and microvessel density as compared with NV1023 and PBS. Excised murine flank tumors treated with NV1042 had decreased subdermal vascularity as compared with NV1023 and PBS. Both splenocytes and IL-12 expression by NV1042 were required for in vitro inhibition of endothelial tubule formation. Conclusions: IL-12 expression by an oncolytic herpes virus enhances therapy of SCC through antiangiogenic mechanisms. Strategies combining HSV oncolysis with angiogenesis inhibition merit further investigation for potential clinical application. |
| Keywords: | signal transduction; controlled study; squamous cell carcinoma; carcinoma, squamous cell; angiogenesis inhibitor; drug efficacy; nonhuman; animal cell; mouse; animals; mice; animal tissue; tumor volume; animal experiment; animal model; hemoglobin; antineoplastic activity; cell line, tumor; transfection; angiogenesis; neovascularization, pathologic; enzyme linked immunosorbent assay; time factors; viral gene delivery system; endothelial cells; blotting, western; gamma interferon; drug mechanism; endothelium, vascular; collagen; oncolytic virus; herpes virus; herpesviridae; matrigel; virus replication; enzyme-linked immunosorbent assay; tumor growth; drug combinations; gamma interferon inducible protein 10; tumor vascularization; interleukin 12; transgenes; laminin; spleen cell; coculture techniques; mice, inbred c3h; interleukin-12; hemoglobin determination; interferon type ii; proteoglycans; herpesvirus vector; chemokines, cxc; virus oncolysate; humans; priority journal; article; monokine |
| Journal Title: | Clinical Cancer Research |
| Volume: | 10 |
| Issue: | 13 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2004-07-01 |
| Start Page: | 4509 |
| End Page: | 4516 |
| Language: | English |
| DOI: | 10.1158/1078-0432.ccr-04-0081 |
| PROVIDER: | scopus |
| PUBMED: | 15240543 |
| DOI/URL: | |
| Notes: | Clin. Cancer Res. -- Cited By (since 1996):54 -- Export Date: 16 June 2014 -- CODEN: CCREF -- Source: Scopus |
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