Genetically targeted radiotherapy for multiple myeloma

David Dingli, Rosa Maria Diaz, Elizabeth R. Bergert, Michael K. O'Connor, John C. Morris, Stephen J. Russell

Research output: Contribution to journalArticle

77 Scopus citations

Abstract

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 enhanced green fluorescent protein (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 nonmyeloma cell lines tested compared with the cytomegalovirus (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 with controls. Tumor xenografts in severe combined immunodeficiency mice expressing hNIS could be imaged using iodine-123 (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 iodine-131 (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.

Original languageEnglish (US)
Pages (from-to)489-496
Number of pages8
JournalBlood
Volume102
Issue number2
DOIs
StatePublished - Jul 15 2003

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Dingli, D., Diaz, R. M., Bergert, E. R., O'Connor, M. K., Morris, J. C., & Russell, S. J. (2003). Genetically targeted radiotherapy for multiple myeloma. Blood, 102(2), 489-496. https://doi.org/10.1182/blood-2002-11-3390