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Inhibition of Radiation-induced Nuclear Factor-B Activation by an Anti-Ras Single-Chain Antibody Fragment

Lack of Involvement in Radiosensitization

Molecular Radiation Therapeutics Branch, Radiation Oncology Science Program, National Cancer Institute, Bethesda, Maryland 20892 [J. S. R., P. J. T.]; Departments of Experimental Radiation Oncology [J. S. R., U. R., G. J. G., P. J. T.] and Neurosurgery [F. F. L., P. J. T.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030; Introgen Therapeutics, Inc., Houston, Texas 77054 [D. R. W.]; and Aventis Pharmaceuticals, Hayward, California 94540 [T. H.]

We have shown previously that the transduction of a number of human tumor cell lines with an adenovirus (AV1Y28) expressing a single-chain antibody fragment (scFv) directed against Ras proteins results in radiosensitization. Because Ras is involved in the regulation of a number of transcription factors, we have determined the effects of this adenovirus on the activation of nuclear factor-B (NF-B), a radiation-responsive transcription factor associated with cell survival. In U251 human glioma cells, radiation-induced NF-B was significantly attenuated by prior transduction of the anti-Ras scFv adenovirus. This effect appeared to involve an inhibition of IB kinase activity and IB phosphorylation. Inhibitors to the Ras effectors mitogen-activated protein kinase kinase, phosphatidylinositol 3-kinase, and p38, however, did not reduce radiation-induced NF-B. Whereas AV1Y28 inhibited NF-B activation by hydrogen peroxide and ferricyanide, it had no effect of tumor necrosis factor--induced NF-B activation. These results are consistent with a novel Ras-dependent, oxidant-specific signaling pathway mediating the activation of NF-B. In additional cell lines radiosensitized by AV1Y28, radiation-induced NF-B activation was also inhibited by the anti-Ras scFv, whereas in cell lines not radiosensitized, radiation did not activate NF-B. This correlation suggested that AV1Y28-mediated radiosensitization involved the inhibition of radiation-induced NF-B activation. However, inhibition of NF-B activation via the expression of a dominant-negative form of IB in U251 cells had no effect on radiation-induced cell killing and did not influence AV1Y28-mediated radiosensitization. Therefore, whereas AV1Y28 inhibits radiation-induced NF-B activation, this process does not appear to play a direct role in its radiosensitizing actions.

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