Genetically targeted radiotherapy for multiple myeloma.
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 sodiumiodide 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.
Dingli
David
D
Mayo Clinic and Foundation, Rochester, MN, USA.
Diaz
Rosa Maria
RM
Bergert
Elizabeth R
ER
O'Connor
Michael K
MK
Morris
John C
JC
Russell
Stephen J
SJ
D000818:Animals; D003587:Cytomegalovirus / Q000235:genetics; D003673:Defective Viruses / Q000235:genetics*; D016503:Drug Delivery Systems; D004742:Enhancer Elements, Genetic; D005803:Genes, Immunoglobulin; D017930:Genes, Reporter; D005813:Genes, Synthetic; D005822:Genetic Vectors / Q000235:genetics / Q000627:therapeutic use*; D049452:Green Fluorescent Proteins; D006801:Humans; D007145:Immunoglobulin kappa-Chains / Q000235:genetics; D007438:Introns / Q000235:genetics; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016086:Lentivirus / Q000235:genetics*; D008164:Luminescent Proteins / Q000235:genetics; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D009194:Myeloma Proteins / Q000235:genetics*; D011401:Promoter Regions, Genetic; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D027981:Symporters / Q000235:genetics* / Q000502:physiology; D014158:Transcription, Genetic; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured / Q000378:metabolism / Q000637:transplantation; D023041:Xenograft Model Antitumor Assays; D000099209:Sodium-Iodide Symporters
D049452:Green Fluorescent Proteins; D007145:Immunoglobulin kappa-Chains; D007457:Iodine Radioisotopes; D008164:Luminescent Proteins; D009194:Myeloma Proteins; D019275:Radiopharmaceuticals; D011993:Recombinant Fusion Proteins; D027981:Symporters; D000099209:Sodium-Iodide Symporters