Bortezomib-induced enzyme-targeted radiation therapy in herpesvirus-associated tumors

Nat Med. 2008 Oct;14(10):1118-22. doi: 10.1038/nm.1864. Epub 2008 Sep 7.


We investigated the possibility of using a pharmacologic agent to modulate viral gene expression to target radiotherapy to tumor tissue. In a mouse xenograft model, we had previously shown targeting of [(125)I]2'-fluoro-2'-deoxy-beta-D-5-iodouracil-arabinofuranoside ([(125)I]FIAU) to tumors engineered to express the Epstein-Barr virus thymidine kinase (EBV-TK). Here we extend those results to targeting of a therapeutic radiopharmaceutical [(131)I]FIAU to slow or stop tumor growth or to achieve tumor regression. These outcomes were achieved in xenografts with tumors that constitutively expressed the EBV-TK. With naturally infected EBV tumor cell lines (Burkitt's lymphoma and gastric carcinoma), activation of viral gene expression by pretreatment with bortezomib was required. Marked changes in tumor growth could also be achieved in naturally infected Kaposi's sarcoma herpesvirus tumors after pretreatment with bortezomib. Bortezomib-induced enzyme-targeted radiation therapy illustrates the possibility of pharmacologically modulating tumor gene expression to result in targeted radiotherapy.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Arabinofuranosyluracil / analogs & derivatives*
  • Arabinofuranosyluracil / therapeutic use
  • Boronic Acids / pharmacology*
  • Bortezomib
  • Burkitt Lymphoma / radiotherapy*
  • Cell Line, Tumor
  • Herpesviridae Infections / radiotherapy
  • Herpesvirus 4, Human / enzymology
  • Humans
  • Iodine Radioisotopes / therapeutic use*
  • Male
  • Mice
  • Mice, SCID
  • Pyrazines / pharmacology*
  • Radiopharmaceuticals / therapeutic use*
  • Sarcoma, Kaposi / radiotherapy
  • Stomach Neoplasms / radiotherapy*
  • Thymidine Kinase / genetics
  • Thymidine Kinase / metabolism*


  • Antineoplastic Agents
  • Boronic Acids
  • Iodine Radioisotopes
  • Pyrazines
  • Radiopharmaceuticals
  • Arabinofuranosyluracil
  • fialuridine
  • Bortezomib
  • Thymidine Kinase