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Melanoma Differentiation-associated 7 (Interleukin 24) Inhibits Growth and Enhances Radiosensitivity of Glioma Cells in Vitro and in Vivo¹

Departments of Radiation Oncology [A. Y., C. M., C. S., R. M., L. Q., P. D.], Neurosurgery [A. L., W. C. B.], Medicine [S. G.], and Biostatistics [V. R.], Virginia Commonwealth University, Richmond, Virginia 23298-0058, and Departments of Pathology [I. V. L., D. S., Z-Z. S., R. G., P. B. F.], Neurosurgery [P. B. F.], and Urology [P. B. F.], College of Physicians and Surgeons, Columbia University, New York, New York 10032

ABSTRACT

Purpose: Despite therapeutic interventions including surgery, chemotherapy, and radiotherapy, glioblastoma multiforme (GBM) has a very poor prognosis and novel therapies are required.

Experimental Design: Melanoma differentiation-associated 7 (mda-7) (interleukin 24), when expressed via a recombinant replication-defective adenovirus, adenovirus (Ad).mda-7, has profound antiproliferative and cytotoxic effects in a variety of tumor cells but not in nontransformed cells. The present studies examined the combined impact of Ad.mda-7 and ionizing radiation on the proliferation and survival of GBM cell lines.

Results: Ad.mda-7 caused a dose-dependent reduction in the proliferation of glioma cells in 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays. The antiproliferative effects of Ad.mda-7 were enhanced by radiation in a greater than additive fashion. These effects were not observed in cultures of nontransformed primary astrocytes. Purified MDA-7 protein caused a similar dose-dependent reduction in GBM cell growth that was enhanced after radiation exposure. The enhanced reduction in growth correlated with increased necrosis and DNA degradation. These modifications in cell phenotype correlated with reduced expression of Bcl-_XL and enhanced expression of BAX. Overexpression of Bcl-_XL protected cells from the antiproliferative and cytotoxic effects of Ad.mda-7 + radiation. Incubation of cells with N-acetyl cysteine abolished the enhancing effects of radiation. In vitro, Ad.mda-7 and radiation reduced colony formation ability, which was significantly increased when the two treatments were combined. In vivo, Ad.mda-7 enhanced the survival of Fischer 344 rats implanted intracranially with glioma cells. Radiation did not alter survival in control infected animals, whereas it prolonged survival in those infected with Ad.mda-7.

Conclusions: These findings demonstrate that mda-7 reduces the proliferation and enhances the radiosensitivity of GBM cells in vitro and in vivo.

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