TY - JOUR
T1 - Carcinoembryonic antigen directed herpes viral oncolysis improves selectivity and activity in colorectal cancer
AU - Reinblatt, Maura
AU - Pin, Richard H.
AU - Fong, Yuman
N1 - Funding Information:
Supported in part by grants RO1 CA 76416 and RO1 CA/DK80982 from the National Institutes of Health, grant MBC-99366 from the American Cancer Society, grant BC024118 from the US Army, and a grant from the Baker Street Foundation.
Copyright:
Copyright 2012 Elsevier B.V., All rights reserved.
PY - 2004/9
Y1 - 2004/9
N2 - 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.
AB - 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.
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U2 - 10.1016/j.surg.2004.05.033
DO - 10.1016/j.surg.2004.05.033
M3 - Article
C2 - 15349105
AN - SCOPUS:4444364267
SN - 0039-6060
VL - 136
SP - 579
EP - 584
JO - Surgery
JF - Surgery
IS - 3
ER -