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Mechanisms of Radioprotection in Hematopoiesis

James R. Zucali, Ph.D.

Interleukin-1 and tumor necrosis factor have previously been shown to protect mice against lethal irradiation. They are also known to induce the expression of the antioxidant enzyme manganese superoxide dismutase (MnSOD) which may be responsible in some part for the radioprotection. The goal of this investigation to determine if up-regulation of MnSOD will confer increased protection in patients from lethal irradiation for hematopoietic cells in order to provide a therapeutic advantage in the selective protection of normal versus malignant cells. To accomplish this, we have shown that transfection of a melanoma cell line with MnSOD in the sense direction will provide increased resistance to irradiation and increased MnSOD message and protein, whereas, transfection of the leukemic cell line K562 with MnSOD in the antisense orientation demonstrates increased sensitivity to irradiation and decreased MnSOD message and protein. Studies are currently underway to transduce normal murine bone marrow stem cells with the gene for MnSOD using both retroviral and AAV vectors to determine if overexpression of this enzyme in hematopoietic stem cells will provide increased protection from an irradiation insult in a lethally irradiated mouse model system. Success with this system would lead to proposing a clinical investigation of inserting the MnSOD gene into human hematopoietic stem cells for protection against irradiation in a bone marrow transplant setting. To accomplish this would require a GMP vector production laboratory and associated personnel in the GCRC and the Gene Therapy Center.

References

  1. Zucali JR. Mechanism of Protection of Hematopoietic Stem Cells from Irradiation. Leukemia and Lymphoma 13:27-32, 1993.
  2. Zucali JR, Moreb J, Gibbons W, Alderman J, Suresh A, Zhang Y, Shelby B. Radioprotection of Hematopoietic Stem Cells by Interleukin-1. Exper. Hematol. 22:130-135, 1994.
  3. Suresh A, Tung F, Moreb J, Zucali JR. Role of Superoxide Dismutase in Radioprotection Using Gene Transfer Studies. Cancer Gene Therapy 1:85-90, 1994.