Sodium iodide symporter (NIS)-mediated radiovirotherapy for pancreatic cancer.

OBJECTIVE We have previously shown the therapeutic efficacy of an engineered oncolytic measles virus expressing the sodium iodide symporter reporter gene (MV-NIS) in mice with human pancreatic cancer xenografts. The goal of this study was to determine the synergy between MV-NIS-induced oncolysis and NIS-mediated (131)I radiotherapy in this tumor model. MATERIALS AND METHODS Subcutaneous human BxPC-3 pancreatic tumors were injected twice with MV-NIS. Viral infection, NIS expression, and intratumoral iodide uptake were quantitated with (123)I micro-SPECT/CT. Mice with MV-NIS-infected tumors were treated with 0, 37, or 74 MBq (131)I and monitored for tumor progression and survival. Additional studies were performed with stable NIS-expressing tumors (BxPC-3-NIS) treated with 0, 3.7, 18.5, 37, or 74 MBq of (131)I. RESULTS Mice treated with intratumoral MV-NIS exhibited significant tumor growth delay (p < 0.01) and prolonged survival (p = 0.02) compared with untreated mice. Synergy between MV-NIS-induced oncolysis and NIS-mediated (131)I ablation was not seen; however, a significant correlation was observed between NIS-mediated intratumoral iodide localization (% ID/g) and peak tumor volume reduction (p = 0.04) with combination MV-NIS and (131)I therapy. Stably transduced NIS-expressing BxPC-3 tumors exhibited rapid regression with > or = 18.5 MBq (131)I. CONCLUSION Delivery of (131)I radiotherapy to NIS-expressing tumors can be optimized using micro-SPECT/CT imaging guidance. Significant hurdles exist for NIS as a therapeutic gene for combined radiovirotherapy in this human pancreatic cancer model. The lack of synergy observed with MV-NIS and (131)I in this model was not due to a lack of radiosensitivity but rather to a nonuniform intratumoral distribution of MV-NIS infection.

[1]  V. Lowe,et al.  In Vivo Quantitation of Intratumoral Radioisotope Uptake Using Micro-Single Photon Emission Computed Tomography/Computed Tomography , 2006, Molecular Imaging and Biology.

[2]  E. Galanis,et al.  Clinical trial results with oncolytic virotherapy: a century of promise, a decade of progress , 2007, Nature Clinical Practice Oncology.

[3]  M. Billeter,et al.  Rescue of measles viruses from cloned DNA. , 1995, The EMBO journal.

[4]  T. Endo,et al.  Iodide uptake and experimental 131I therapy in transplanted undifferentiated thyroid cancer cells expressing the Na+/I- symporter gene. , 1997, Endocrinology.

[5]  D. Tindall,et al.  In vivo sodium iodide symporter gene therapy of prostate cancer , 2001, Gene Therapy.

[6]  D. Kirn,et al.  Gene therapy progress and prospects cancer: oncolytic viruses , 2008, Gene Therapy.

[7]  S. Russell,et al.  Dual Therapy of Ovarian Cancer Using Measles Viruses Expressing Carcinoembryonic Antigen and Sodium Iodide Symporter , 2006, Clinical Cancer Research.

[8]  A. Pinchera,et al.  Treatment with drugs able to reduce iodine efflux significantly increases the intracellular retention time in thyroid cancer cells stably transfected with sodium iodide symporter complementary deoxyribonucleic acid. , 2006, The Journal of clinical endocrinology and metabolism.

[9]  M. O’Connor,et al.  Image-guided radioiodide therapy of medullary thyroid cancer after carcinoembryonic antigen promoter-targeted sodium iodide symporter gene expression. , 2007, Human gene therapy.

[10]  B. Kemp,et al.  Quantitative molecular imaging of viral therapy for pancreatic cancer using an engineered measles virus expressing the sodium-iodide symporter reporter gene. , 2009, AJR. American journal of roentgenology.

[11]  E. Galanis,et al.  Clinical testing of engineered oncolytic measles virus strains in the treatment of cancer: an overview. , 2009, Current opinion in molecular therapeutics.

[12]  M. O’Connor,et al.  Adenovirus-mediated and targeted expression of the sodium-iodide symporter permits in vivo radioiodide imaging and therapy of pancreatic tumors. , 2006, Human gene therapy.

[13]  P. Opolon,et al.  Adenovirus-mediated transfer of the thyroid sodium/iodide symporter gene into tumors for a targeted radiotherapy. , 2000, Cancer research.

[14]  C. Bassi,et al.  Radiotherapy and chemotherapy in pancreatic cancer. Topical issues and future perspectives. , 2006, JOP : Journal of the pancreas.

[15]  U. Haberkorn,et al.  Radioiodine therapy of hepatoma using targeted transfer of the human sodium/iodide symporter gene. , 2006, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[16]  R. Vile,et al.  Clinical review 132: The sodium iodide symporter and its potential role in cancer therapy. , 2001, The Journal of clinical endocrinology and metabolism.

[17]  T. Petrich,et al.  Establishment of radioactive astatine and iodine uptake in cancer cell lines expressing the human sodium/iodide symporter , 2002, European Journal of Nuclear Medicine and Molecular Imaging.

[18]  S. H. Wollman,et al.  Kinetics of accumulation of radio-iodine by thyroid gland: short time intervals. , 1962, The American journal of physiology.

[19]  Li Zhu,et al.  Ectopic expression of the thyroperoxidase gene augments radioiodide uptake and retention mediated by the sodium iodide symporter in non–small cell lung cancer , 2001, Cancer Gene Therapy.

[20]  S. Russell,et al.  Measles virus for cancer therapy. , 2009, Current topics in microbiology and immunology.

[21]  D. Dingli,et al.  In vivo imaging and tumor therapy with the sodium iodide symporter , 2003, Journal of cellular biochemistry.

[22]  R. Mandell,et al.  Radioisotope concentrator gene therapy using the sodium/iodide symporter gene. , 1999, Cancer research.

[23]  Goulven Merer,et al.  Small‐Molecule Inhibitors of Sodium Iodide Symporter Function , 2008, Chembiochem : a European journal of chemical biology.

[24]  L. Mollet,et al.  A Molecularly Cloned Schwarz Strain of Measles Virus Vaccine Induces Strong Immune Responses in Macaques and Transgenic Mice , 2003, Journal of Virology.

[25]  S. Russell,et al.  Measles virus as an oncolytic vector platform. , 2008, Current gene therapy.

[26]  David Dingli,et al.  Genetically targeted radiotherapy for multiple myeloma. , 2003, Blood.

[27]  D. Trono,et al.  Self-Inactivating Lentivirus Vector for Safe and Efficient In Vivo Gene Delivery , 1998, Journal of Virology.

[28]  G. Gores,et al.  Treatment options for hepatobiliary and pancreatic cancer. , 2007, Mayo Clinic proceedings.

[29]  S. Derbré,et al.  Synthesis and evaluation of photoreactive probes to elucidate iodide efflux in thyrocytes. , 2009, Bioorganic & medicinal chemistry letters.

[30]  D. Dingli,et al.  Image-guided radiovirotherapy for multiple myeloma using a recombinant measles virus expressing the thyroidal sodium iodide symporter. , 2004, Blood.

[31]  Christoph Michalski,et al.  Pancreatic Cancer: From Bench to 5-Year Survival , 2006, Pancreas.

[32]  H. Sakahara,et al.  Establishment and characterization of a breast cancer cell line expressing Na+/I- symporters for radioiodide concentrator gene therapy. , 2000, Journal of nuclear medicine : official publication, Society of Nuclear Medicine.

[33]  Stephen L. Brown,et al.  Phase I study of noninvasive imaging of adenovirus-mediated gene expression in the human prostate. , 2008, Molecular therapy : the journal of the American Society of Gene Therapy.

[34]  D. Tindall,et al.  Treatment of prostate cancer by radioiodine therapy after tissue-specific expression of the sodium iodide symporter. , 2000, Cancer research.

[35]  N. LaRusso,et al.  Engineered measles virus as a novel oncolytic viral therapy system for hepatocellular carcinoma , 2006, Hepatology.

[36]  D. Kirn,et al.  Oncolytic adenoviruses for cancer gene therapy. , 2008, Methods in molecular biology.