Targeted Radionuclide Therapy: A Historical and Personal Review

Semin Nucl Med. 2020 Jan;50(1):87-97. doi: 10.1053/j.semnuclmed.2019.07.006. Epub 2019 Nov 6.


This review traces the development of targeted radionuclide therapy (TRT) (the Magic Bullet) from the discovery of radioactivity in nature and the subsequent discovery of artificial radioactivity (the production of radioactive isotopes of stable elements) to the current status of TRT in the medical literature and clinical practice. With the availability of radioisotopes of iodine, initially to study thyroidal iodine kinetics, it was soon observed that sufficient amounts of radiation could control thyroid hyperfunction. Shortly thereafter, when radioiodine was administered to a patient with differentiated thyroid carcinoma whose hypermetabolism was secondary to excess thyroid hormone production, it was observed that radioiodine also had an antitumor effect. The concept of the Magic Bullet has since been extended to other disease states such as (1) 131I-meta-iodobenzylguanidine (131I-MIBG) to treat malignant and metastatic pheochromocytomas and paragangliomas; (2) 131I-tositumomab, a radioiodinated anti-CD20 IgG to treat CD20 expressing non-Hodgkins lymphoma. In recent years, other β-emitting radionuclides, Yttrium-90 (90Y) and Lutetium-177 (177Lu), have been added to this list. These radiometals have different physical properties that were thought to be possibly more effective than radioiodine. 90Y was initially used to radio-label somatostatin analogues to treat metastatic neuroendocrine tumors but has virtually been replaced by 177Lu since the physical characteristics of the latter appear to be better suited to effectively irradiate the micrometastases of neuroendocrine tumors. A similar evolution is taking place in the development of a targeted radionuclide therapeutic that recognizes prostate-specific membrane antigen (PSMA), an epitope expressed in increased amounts in prostate carcinoma. Both an anti-PSMA immunoglobulin (J591) and a small molecule glutamase ligand are currently being evaluated as targeted radionuclide therapy agents. Radionuclides that have affinity for the calcium hydroxyapatite in bone have been used to relieve bone pain due to tumor metastases based on increased deposition of the bone seeking radiometals at the osteoblastic interface of the tumor metastases and boney matrix. Most of these trials have been in patients with metastatic prostate cancer since there are few other options. In this regard, targeted radionuclide therapy has come full circles as the most recent addition to this anti-tumor arsenal is a radioisotope of Radium, 223Ra, an alpha emitter which has a greater radiobiologic effect but limited range in tissue thus adding an element of safety when treating marrow metastases. Other alpha emitting radiometals are currently being evaluated as alternative radiometals in place of 90Y and 177Lu to label targeting molecules.

Publication types

  • Historical Article
  • Review

MeSH terms

  • History, 20th Century
  • History, 21st Century
  • Humans
  • Neoplasms / radiotherapy
  • Radiotherapy / history*