title: Radiolabeled 5-iodo-3'-O-(17beta-succinyl-5alpha-androstan-3-one)-2'-deoxyuridine and its 5'-monophosphate for imaging and therapy of androgen receptor-positive cancers: synthesis and biological evaluation.
abstract: High levels of androgen receptor (AR) are often indicative of recurrent, advanced, or metastatic cancers. These conditions are also characterized by a high proliferative fraction. 5-Radioiodo-3'-O-(17beta-succinyl-5alpha-androstan-3-one)-2'-deoxyuridine 8 and 5-radioiodo-3'-O-(17beta-succinyl-5alpha-androstan-3-one)-2'-deoxyuridin-5'-yl monophosphate 13 target AR. They are also degraded intracellularly to 5-radioiodo-2'-deoxyuridine 1 and its monophosphate 20, respectively, which can participate in the DNA synthesis. Both drugs were prepared at the no-carrier-added level. Precursors and methods are readily adaptable to radiolabeling with various radiohalides suitable for SPECT and PET imaging, as well as endoradiotherapy. In vitro and in vivo studies confirm the AR-dependent interactions. Both drugs bind to sex hormone binding globulin. This binding significantly improves their stability in serum. Biodistribution and imaging studies show preferential uptake and retention of 8 and 13 in ip xenografts of human ovarian adenocarcinoma cells NIH:OVCAR-3, which overexpress AR. When these drugs are administered at therapeutic dose levels, a significant tumor growth arrest is observed.
authors: Department of Radiation Oncology, J. Bruce Henriksen Cancer Research Laboratories, University of Nebraska Medical Center, 986850 Nebraska Medical Center, Omaha, Nebraska 68198-6850, USA. zkortylewicz@unmc.edu
authors: Zbigniew P
authors: ZP
authors: Kortylewicz
authors: Jessica
authors: J
authors: Nearman
authors: Janina
authors: J
authors: Baranowska-Kortylewicz
mesh_terms: D000732:Androstanols / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003856:Deoxyuracil Nucleotides / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D003857:Deoxyuridine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007457:Iodine Radioisotopes; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy* / Q000378:metabolism; D011485:Protein Binding; D011817:Rabbits; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D011944:Receptors, Androgen / Q000378:metabolism*; D044967:Serum; D012738:Sex Hormone-Binding Globulin / Q000737:chemistry; D014183:Transplantation, Heterologous
chemical_list: C550439:5-iodo-3'-O-(17beta-succinyl-5alpha-androstan-3-one)-2'-deoxyuridine; C550440:5-iodo-3'-O-(17beta-succinyl-5alpha-androstan-3-one)-2'-deoxyuridine 5'-monophosphate; D000732:Androstanols; D001798:Blood Proteins; D003856:Deoxyuracil Nucleotides; D007457:Iodine Radioisotopes; D019275:Radiopharmaceuticals; D011944:Receptors, Androgen; D012738:Sex Hormone-Binding Globulin; D003857:Deoxyuridine