Adenovirus gene transfer vectors inhibit growth of lymphatic tumor metastases independent of a therapeutic transgene Journal Article
| Authors: | Korst, R. J.; Ailawadi, M.; Lee, J. M.; Lee, S.; Yamada, R.; Mahtabifard, A.; Crystal, R. G. |
| Article Title: | Adenovirus gene transfer vectors inhibit growth of lymphatic tumor metastases independent of a therapeutic transgene |
| Abstract: | Adenovirus (Ad) gene transfer vectors traffic to regional lymph nodes (RLNs) after footpad injections in mice, resulting in localized production of interferon γ (IFN-γ). With this background, we evaluated the hypothesis that Ad vector administration may inhibit RLN tumor metastasis independent of the transgene in the expression cassette. Tumors of MM48, a cell line with a propensity toward lymphogenous metastasis, were established in the footpads of syngeneic C3H mice, and E1-E3- Ad vectors encoding no transgene (AdNull) or encoding an irrelevant transgene (AdCD; Escherichia coli cytosine deaminase with no 5-fluorocytosine administration) were administered (1010 particles) in a peritumoral location. Both vectors suppressed the growth of tumor in the regional (popliteal) lymph node. This effect was localized to the regional, but not distant, lymph nodes (p < 0.05). Heat inactivation of the vector or decreasing the dose of the vector to 109 particles did not suppress RLN growth of the tumor when compared with 1010 particles of active AdNull (p < 0.05 and p < 0.01, respectively). The ability of an E1-E4- vector expressing β-galactosidase (AdRSVβgal.11) to suppress RLN tumor growth showed that the E4 region of the Ad vector was not responsible for the effect. Blocking either IFN-γ or natural killer (NK) cells with systemic antibody treatment in immunocompetent mice allowed rapid growth of RLN metastases despite Ad vector administration, and Ad vector injection into the footpads of tumor-free mice induced the accumulation of NK cells in the RLN. These data demonstrate that, in a metastatic murine tumor model, a low dose (1010 particles) of replication-deficient Ad vectors inhibits RLN metastases independent of a therapeutic transgene, an effect that is mediated, at least in part, by IFN-γ and NK cells. |
| Keywords: | controlled study; human cell; sequence deletion; dose response; nonhuman; flow cytometry; lymph node metastasis; lymph nodes; lymphatic metastasis; mouse; animals; mice; animal tissue; cell division; gene expression; animal experiment; animal model; cancer cell culture; tumor cells, cultured; time factors; gene transfer; genetic vectors; cancer inhibition; gamma interferon; lymph node; escherichia coli; gene therapy; transgene; beta galactosidase; foot pad; natural killer cell; killer cells, natural; transgenes; immunocompetence; adenoviridae; virus vector; mice, inbred c3h; cytosine deaminase; flucytosine; gene cassette; adenovirus; virus gene; metastasis inhibition; gamma interferon antibody; interferon type ii; human; male; article; virus inactivation |
| Journal Title: | Human Gene Therapy |
| Volume: | 12 |
| Issue: | 13 |
| ISSN: | 1043-0342 |
| Publisher: | Mary Ann Liebert, Inc |
| Date Published: | 2001-09-01 |
| Start Page: | 1639 |
| End Page: | 1649 |
| Language: | English |
| DOI: | 10.1089/10430340152528138 |
| PUBMED: | 11535167 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Export Date: 21 May 2015 -- Source: Scopus |
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