Utilizing tumor hypoxia to enhance oncolytic viral therapy in colorectal metastases Journal Article
| Authors: | Reinblatt, M.; Pin, R. H.; Federoff, H. J.; Fong, Y. |
| Article Title: | Utilizing tumor hypoxia to enhance oncolytic viral therapy in colorectal metastases |
| Abstract: | Objective: To determine the effects of hypoxia-induced ribonucleotide reductase (RR) production on herpes oncolytic viral therapy. Summary Background Data: Hypoxia is a common tumor condition correlated with therapeutic resistance and metastases. Attenuated viruses offer a unique cancer treatment by specifically infecting and lysing tumor cells. G207 is an oncolytic herpes virus deficient in RR, a rate-limiting enzyme for viral replication. Methods: A multimerized hypoxia-responsive enhancer was constructed (10xHRE) and functionally tested by luciferase assay. 10xHRE was cloned upstream of UL39, the gene encoding the large subunit of RR (10xHRE-UL39). CT26 murine colorectal cancer cells were transfected with 10xHRE-UL39, incubated in hypoxia (1% O 2) or normoxia (21% O2), and infected with G207 for cytotoxicity assays. CT26 liver metastases, with or without 10xHRE-UL39, were created in syngeneic Balb/C mice (n = 40). Livers were treated with G207 or saline. Tumors were assessed and stained immunohistochemically for G207. Results: 10xHRE increased luciferase expression 33-fold in hypoxia versus controls (P < 0.001). In normoxia, 10xHRE-UL39 transfection did not improve G207 cytotoxicity. In hypoxia, G207 cytotoxicity increased 87% with 10xHRE-UL39 transfection versus nontransfected cells (P < 0.001). CT26 were resistant to G207 alone. Combining 10xHRE-UL39 with G207 resulted in a 66% decrease in tumor weights (P < 0.0001) and a 65% reduction in tumor nodules (P < 0.0001) versus G207 monotherapy. 10xHRE-UL39-transfected tumors demonstrated greater viral staining. Conclusions: Hypoxia-driven RR production significantly enhances viral cytotoxicity in vitro and reduces tumor burden in vivo. G207 combined with RR under hypoxic control is a promising treatment for colorectal cancer, which would otherwise be resistant to oncolytic herpes virus alone. |
| Keywords: | immunohistochemistry; vasculotropin; controlled study; nonhuman; liver neoplasms; conference paper; sensitivity and specificity; polymerase chain reaction; colorectal cancer; animal cell; mouse; animals; mice; cell survival; metastasis; gene expression; animal model; cancer cell culture; cytotoxicity; enzyme activity; cell line, tumor; cancer therapy; genetic vectors; hypoxia; colorectal neoplasms; liver metastasis; molecular sequence data; nucleotide sequence; gene therapy; oncolytic virus; herpes virus; oncolytic virotherapy; base sequence; herpesvirus 1, human; virus replication; tumor growth; hypoxia inducible factor 1alpha; oligonucleotide; anoxia; growth inhibition; enhancer region; ribonucleotide reductase; priority journal; herpes virus g207 |
| Journal Title: | Annals of Surgery |
| Volume: | 239 |
| Issue: | 6 |
| ISSN: | 0003-4932 |
| Publisher: | Lippincott Williams & Wilkins |
| Date Published: | 2004-06-01 |
| Start Page: | 892 |
| End Page: | 902 |
| Language: | English |
| DOI: | 10.1097/01.sla.0000128308.36393.38 |
| PROVIDER: | scopus |
| PMCID: | PMC1356298 |
| PUBMED: | 15166969 |
| DOI/URL: | |
| Notes: | Ann. Surg. -- Cited By (since 1996):17 -- Export Date: 16 June 2014 -- CODEN: ANSUA -- Source: Scopus |
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