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Prepublished online as a Blood First Edition Paper on March 20, 2003; DOI 10.1182/blood-2002-11-3390.
Submitted November 8, 2002
Accepted March 13, 2003
Genetically targeted radiotherapy for multiple myeloma
David Dingli, Rosa Maria Diaz, Elizabeth R Bergert, Michael K O'Connor, John C Morris, and Stephen J Russell*
Molecular Medicine Program, Mayo Clinic, Rochester, MN, USA
Division of Hematology, Mayo Clinic, Rochester, MN, USA
Division of Endocrinology, Mayo Clinic, Rochester, MN, USA
Department of Radiology, Mayo Clinic, Rochester, MN, USA
* Corresponding author; email: sjr{at}mayo.edu.
Multiple myeloma is a disseminated neoplasm of terminally differentiated plasma cells that is incurable with currently available therapies. Although the disease is radiosensitive, external beam radiation leads to significant toxicity due to sensitive end-organ damage. Thus, genetic approaches for therapy are required. We hypothesized that the incorporation of immunoglobulin promoter and enhancer elements in a self-inactivating (SIN) lentiviral vector should lead to specific and high-level transgene expression in myeloma cells. A SIN lentivector with EGFP expression under the control of a minimal immunoglobulin promoter as well as the Kappa light chain intronic and 3' enhancers transduced myeloma cell lines with high efficiency (30 - 90%). EGFP was expressed at a high level in myeloma cells but silent in all non-myeloma cell lines tested compared to the CMV promoter/enhancer. Transduction of myeloma cells with the targeted vector coding for the human sodium iodide symporter (hNIS) led to hNIS expression by these cells allowing them to concentrate radioiodine up to 18 fold compared to controls. Tumor xenografts in SCID mice expressing hNIS could be imaged using 123I and shown to retain iodide for up to 48 hours. These tumor xenografts were completely eradicated by a single dose of the therapeutic isotope 131I without evidence of recurrence up to 5 months after therapy. We conclude that lentivectors can be transcriptionally targeted for myeloma cells and the use of hNIS as a therapeutic gene for myeloma in combination with 131I needs further exploration.
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