Carcinoembryonic antigen directed herpes viral oncolysis improves selectivity and activity in colorectal cancer

Maura Reinblatt, Richard H. Pin, Yuman Fong

Research output: Contribution to journalArticlepeer-review

Abstract

G207 is an oncolytic herpes virus whose replicative cycle requires cellular ribonucleotide reductase (RR) for viral DNA synthesis. We attempt to enhance viral cytotoxicity in carcinoembryonic antigen (CEA)-producing colorectal cancer (CRC) cells through CEA-driven RR production.CEA enzyme-linked immunosorbent assay was performed on LS174T and HCT-8 human CRC cells. The CEA enhancer-promoter (CEA E-P) was functionally assessed by luciferase assay. CEA E-P was cloned upstream of UL39, the gene encoding the large subunit of RR. Cells were transfected with CEA E-P/UL39 and infected with G207 for cytotoxicity assays. LS174T, with or without CEA E-P/UL39, were implanted into athymic mouse flanks (n = 28) and treated with G207.CEA levels were 7-fold higher in LS174T versus HCT-8 (P <. 00001). CEA E-P increased luciferase expression 7.5-fold in LS174T (P <. 01), with no increase in HCT-8. G207 cytotoxicity of'CEA E-P/UL39-transfected LS174T cells increased 69% by day 10 versus nontransfected cells (P <. 001), with no significant increase in HCT-8. Combining CEA E-P/UL39 with G207 in LS174T flank tumors resulted in a 65% decrease in tumor volume versus G207, phosphate-buffered saline, or'CEA E-P/UL39 alone (P <. 0001).CEA-driven RR production by CEA-secreting CRC cells significantly improves oncolytic viral cytotoxicity and specificity in vitro, and reduces tumor burden in vivo.

Original languageEnglish (US)
Pages (from-to)579-584
Number of pages6
JournalSurgery
Volume136
Issue number3
DOIs
StatePublished - Sep 2004

ASJC Scopus subject areas

  • Surgery

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