Abstract
Intravascular delivery (1.5 × 109 particles and higher) of recombinant adenovirus (rAd) induces myeloid cell mediated, self-limiting hemodynamic responses in normal mice. However, we observed anaphylactoid-type reactions and exacerbated hemodynamic events following rAd injection in mice bearing malignant 4T1 mammary carcinoma. Because 4T1 tumors induce significant CD11b+Gr-1+ myeloid cell expansion and activation, we set to determine whether this causes rAd-induced exaggerated responses. When treated with a single intravenous dose (1 × 1010 particles) of rAd, mice implanted with 4T1 carcinoma succumbed due to the anaphylactoid-type reactions. In contrast, normal mice and mice implanted with a related mammary carcinoma (66cl4) that does not induce CD11b+ Gr-1+ cell expansion, showed minimal responses. Depletion of phagocytic CD11b+Gr-1+ cells prior to rAd delivery protected 4T1 tumor-bearing animals, whereas passive transfer of CD11b+Gr-1+ cells from 4T1 tumor-bearing animals was sufficient to convey susceptibility to anaphylactoid-type reactions in normal animals. We further show that there is upregulation of nitric oxide and leukotriene signaling pathways in the 4T1 tumor-induced CD11b+Gr-1+ myeloid cells and that pretreating mice with inhibitors of nitric oxide synthetase and leukotrienes can attenuate the anaphylactoid-type reactions. These data show that malignant tumor growth can alter CD11b+Gr-1+ myeloid cells, rendering hosts susceptible to anaphylactoid-type reactions upon intravascular treatment with rAd.
Original language | English (US) |
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Pages (from-to) | 508-515 |
Number of pages | 8 |
Journal | Molecular Therapy |
Volume | 17 |
Issue number | 3 |
DOIs | |
State | Published - 2009 |
ASJC Scopus subject areas
- Molecular Medicine
- Molecular Biology
- Genetics
- Pharmacology
- Drug Discovery