Tissue disposition of 5-o-carboranyluracil--a novel agent for the boron neutron capture therapy of prostate cancer.
The carboranyl nucleotides beta-D-5-o-carboranyl-2'-deoxyuridine (D-CDU), 1-(beta-L-arabinosyl)-5-o-carboranyluracil (D-ribo-CU) and the nucleotide base 5-o-carboranyluracil (CU), were developed as sensitizers for boron neutron capture therapy (BNCT). A structure activity study was initiated to determine the agent most suitable for targeting prostate tumors. Cellular accumulation studies were performed using LNCaP human prostate tumor cells, and the respective tumor disposition profiles were investigated in male nude mice bearing LNCaP and 9479 human prostate tumor xenografts in their flanks. D-CDU achieved high cellular concentrations in LNCaP cells and up to 2.5% of the total cellular compound was recovered in the 5'-monophosphorylated form. In vivo concentrations of D-CDU were similar in LNCaP and 9479 tumor xenografts. Studies in 9479 xenografted bearing mice indicated that increasing the number of hydroxyl groups in the sugar moeity of the carboranyl nucleosides corresponded with an increased rate and extent of renal elimination, shorter serum half-lives and an increased tissue specificity. Tumor/normal prostate ratios were greatest with the nucleoside base CU. These studies indicate that similar nucleoside analogues and bases may have different tissue affinities and retention properties, which should be considered when selecting agents for sensitizing specific tumors for eventual BNCT treatment. CU was found to be the most suitable compound for further development to treat prostate cancer.
Schinazi
Raymond F
RF
Department of Pediatrics, Emory University, Atlanta, Georgia, USA. rschina@emory.edu
Hurwitz
Selwyn J
SJ
Liberman
Irina
I
Glazkova
Yuliya
Y
Mourier
Nicolas S
NS
Olson
Jeffrey
J
Keane
Thomas
T
D000818:Animals; D001896:Boron Compounds / Q000493:pharmacokinetics; D016754:Boron Neutron Capture Therapy; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009928:Organ Specificity; D011467:Prostate / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000532:radiotherapy*; D013997:Time Factors; D014498:Uracil / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics
D001896:Boron Compounds; D014498:Uracil