title: Co-targeting androgen receptor and DNA for imaging and molecular radiotherapy of prostate cancer: in vitro studies.
abstract: BACKGROUND
  The androgen receptor (AR) axis, the key growth and survival pathway in prostate cancer, remains a prime target for drug development. 5-Radioiodo-3'-O-(17β-succinyl-5α-androstan-3-one)-2'-deoxyuridin-5'-yl phosphate (RISAD-P) is the AR-seeking reagent developed for noninvasive assessment of AR and proliferative status, and for molecular radiotherapy of prostate cancer with Auger electron-emitting radionuclides.
  
  
  METHODS
  RISAD-P radiolabeled with 123I, 124I, and 125I were synthesized using a common stannylated precursor. The cellular uptake, subcellular distribution, and radiotoxicity of 123I-, 124I-, and (125) IRISAD-P were measured in LNCaP, DU145, and PC-3 cell lines expressing various levels of AR.
  
  
  RESULTS
  The uptake of RISAD-P by prostate cancer cells is proportional to AR levels and independent of the radionuclide. The intracellular accumulation of radioactivity is directly proportional to the extracellular concentration of RISAD-P and the duration of exposure. Initially, RISAD-P is trapped in the cytoplasm. Within 24 hr, radioactivity is associated exclusively with DNA. The RISAD-P radiotoxicity is determined by the radionuclide; however, the cellular responses are directly proportional to the AR expression levels. LNCaP cells expressing high levels of AR are killed at the rate of up to 60% per day after a brief 1 hr RISAD-P treatment. For the first time, the AR expression in PC-3 and DU 145 cells, generally reported as AR-negative, was quantitated by the ultra sensitive RISAD-P-based method.
  
  
  CONCLUSIONS
  RISAD-P is a theranostic drug, which targets AR. Its subcellular metabolite participates in DNA synthesis. RISAD-P is a promising candidate for imaging of the AR expression and tumor proliferation as well as molecular radiotherapy of prostate cancer.
authors.affiliation: Department of Radiation Oncology, J. Bruce Henriksen Cancer Research Laboratories, University of Nebraska Medical Center, Nebraska.
authors.forename: Guang
authors.initials: G
authors.lastname: Han
authors.forename: Zbigniew P
authors.initials: ZP
authors.lastname: Kortylewicz
authors.forename: Thomas
authors.initials: T
authors.lastname: Enke
authors.forename: Janina
authors.initials: J
authors.lastname: Baranowska-Kortylewicz
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology / Q000532:radiotherapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000528:radiation effects; D004273:DNA, Neoplasm / Q000378:metabolism*; D004307:Dose-Response Relationship, Radiation; D006801:Humans; D066298:In Vitro Techniques; D007457:Iodine Radioisotopes; D008297:Male; D058990:Molecular Targeted Therapy; D011467:Prostate / Q000000981:diagnostic imaging / Q000473:pathology; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000532:radiotherapy*; D011877:Radionuclide Imaging; D061089:Radiotherapy, Image-Guided; D011944:Receptors, Androgen / Q000378:metabolism*
chemical_list: D004273:DNA, Neoplasm; D007457:Iodine Radioisotopes; D011944:Receptors, Androgen
keywords: Auger electrons; androgen receptor; molecular radiotherapy; prostate cancer; theranostic