TY - JOUR
T1 - Radiolabeled 5-iodo-3′-O-(17β-succinyl-5α-androstan-3-one) -2′-deoxyuridine and its 5′-monophosphate for imaging and therapy of androgen receptor-positive cancers
T2 - Synthesis and biological evaluation
AU - Kortylewicz, Zbigniew P.
AU - Nearman, Jessica
AU - Baranowska-Kortylewicz, Janina
PY - 2009/8/27
Y1 - 2009/8/27
N2 - 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-(17β-succinyl-5α- androstan-3-one)-2′-deoxyuridine 8 and 5-radioiodo-3′-O-(17β- succinyl-5α-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.
AB - 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-(17β-succinyl-5α- androstan-3-one)-2′-deoxyuridine 8 and 5-radioiodo-3′-O-(17β- succinyl-5α-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.
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U2 - 10.1021/jm9005803
DO - 10.1021/jm9005803
M3 - Article
C2 - 19653647
AN - SCOPUS:69049110970
SN - 0022-2623
VL - 52
SP - 5124
EP - 5143
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 16
ER -