| Title | Hypoxia-mediated apoptosis from angiogenesis inhibition underlies tumor control by recombinant interleukin 12. | | Author(s) | Gee MS, Koch CJ, Evans SM, Jenkins WT, Pletcher CH, Moore JS, Koblish HK, Lee J, Lord EM, Trinchieri G, Lee WM | | Institution | Biomedical Graduate Program, University of Pennsylvania, Philadelphia 19104, USA. | | Source | Cancer Res 1999 Oct 1; 59(19):4882-9. | | MeSH | Animals
Apoptosis
Cell Hypoxia
Collagen
Drug Combinations
Female
Interferon-gamma, Recombinant
Interleukin-12
Ischemia
Laminin
Melanoma, Experimental
Mice
Mice, Inbred C3H
Neovascularization, Pathologic
Proteoglycans
Recombinant Proteins
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Tumor Cells, Cultured
| | Abstract | The role of angiogenesis inhibition in the antitumor activity of recombinant murine interleukin 12 (rmIL-12) was studied in K1735 murine melanomas, the growth of which is rapidly and markedly suppressed by rmIL-12 treatment. On the basis of the prediction that tumor ischemia should result from therapeutic angiogenesis inhibition, tumor cell hypoxia was evaluated as a marker of ischemia using the EF5 [2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl)aceta mide] approach. This method measures intracellular binding of the nitroimidazole EF5, which covalently binds to cellular macromolecules selectively under hypoxic conditions. Whereas 1 week of rmIL-12 treatment effectively inhibited K1735 cell-induced angiogenesis in Matrigel neovascularization assays, 2 weeks of treatment were needed before severe tumor cell hypoxia was detected in K1735 tumors. The hypoxia that developed was regional and localized to tumor areas distant from blood vessels. The great majority of severely hypoxic tumor cells were apoptotic, and in vitro studies indicated that the degree of hypoxia present within treated tumors was sufficient to trigger K1735 apoptosis. Tumor cell apoptosis was also prevalent in the first week of rmIL-12 treatment when few cells were hypoxic. In vitro studies indicated that this non-hypoxia-related apoptosis was induced directly by IFN-gamma produced in response to rmIL-12 administration. These studies reveal that rmIL-12 controls K1735 tumors initially by IFN-gamma-induced apoptosis and later by hypoxia-induced apoptosis. They also establish hypoxia as an expected result of tumor angiogenesis inhibition and a mediator of its therapeutic effect. | | Language | eng | | Pub Type(s) | Journal Article
| | PubMed ID | 10519400 |
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