CycloSal-dRFIB, a Thymidine Mimetic, Thymidine Kinase by-Pass Nucleoside Prodrug: Radioiodination, in vitro Cellular Uptake and Biodistribution in Murine Models

Author(s): Anke Stahlschmidt, William Sun, Aihua Zhou, Hans-Jurgen Machulla, Edward E. Knaus, Leonard I. Wiebe

Journal Name: Current Radiopharmaceuticals

Volume 3 , Issue 4 , 2010

Become EABM
Become Reviewer
Call for Editor


Cyclo-(3-methylsaligenyl)-5-O-[1-(2,4-difluoro-5-[125I]iodophenyl)-2-deoxy-β-D-ribofuranosyl]phosphate (cycloSal- dRF[125I]IB) was radioiodinated with sodium [125I]iodide via copper-catalyzed isotope exchange in 48% radiochemical yield. cycloSal-dRF[125I]IB was found to be incorporated into the cytoplasmic nucleic acid and mitochondrial fractions of murine KBALB and K-STK (engineered to express HSV-1 thymidine kinase) cells in cell culture. Uptake was greater than that for either the corresponding nucleoside dRF[125I]IB or [125I]IUdR. These in vitro studies support a mechanism of metabolic activation to the free nucleotide, thereby effecting TK-bypass. Pharmacokinetic studies in rats reflect a complex interplay of tissue depot effects, hepatobiliary recycling, and metabolism. Biodistribution studies in tumor- bearing mice provide further evidence for lipophilic depot effects and hepatobiliary recirculation, with no evidence for active (metabolic) accumulation in any tissue.

Keywords: Iododeoxyuridine, difluorophenyldeoxyribosides, prodrugs, thymidine kinase (TK) by-pass, pharmacokinetics, biodistribution, mitochondrial uptake, CycloSal-dRFIB, Thymidine, Thymidine Kinase by-Pass, Murine Models, cycloSal-dRF[I]IB, HSV-1 thymidine kinase, dRF[I]IB, [I]IUdR, pyrimidine nucleosides, phosphorylation, nucleoside kinases, nucleotides, monophosphate, cyclosaligenyl phosphodiester pronucleotides, Xenopus oocytes, fluorodeoxyuridine, cycloSal-dRFIB, , Tris-acetate-EDTA buffer, Coomassie blue G250 reagent, ELISA, BSA, bovine plasma albumin, radioassay, EMT6 tumour cells, (CO asphyxiation), gamma scintillation counter, Cell Culture

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2010
Published on: 01 March, 2012
Page: [267 - 274]
Pages: 8
DOI: 10.2174/1874471011003040267
Price: $65

Article Metrics

PDF: 3