Biodistribution and metabolism of a mixed backbone oligonucleotide (GEM 231) following single and multiple dose administration in mice.
Biodistribution and metabolism of a mixed backbone oligonucleotide (MBO), GEM 231, targeted to the RIalpha subunit of protein kinase A has been studied in normal and tumor xenografted mice. The study has been carried out using [35S]-labeled MBO following single and multiple administrations of doses varying from 2 to 50 mg/kg. MBO showed wide tissue distribution following intravenous and subcutaneous administration. The highest concentration of MBO was in the kidney and liver. The general disposition of MBO was followed by digitized autoradiographic pictures of tumored mice and further confirmed wide tissue disposition and also showed defined intratumor uptake of MBO. Multiple dose administration showed increased disposition in the majority of the tissues/organs, with the exception of the kidneys. Analysis of the extracted MBO by polyacrylamide gel electrophoresis (PAGE) showed the presence of primarily intact MBO along with its degraded forms. Based on our radioactivity levels, the primary route of excretion was in urine, analysis of which showed mainly degraded forms of MBO.
Rusckowski
M
M
Department of Radiology, University of Massachusetts Medical School, Worcester 01655, USA.
Qu
T
T
Roskey
A
A
Agrawal
S
S
D000818:Animals; D001345:Autoradiography; D017868:Cyclic AMP-Dependent Protein Kinases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009368:Neoplasm Transplantation; D020319:Oligodeoxyribonucleotides, Antisense / Q000008:administration & dosage* / Q000097:blood / Q000378:metabolism* / Q000652:urine; D013462:Sulfur Radioisotopes
D020319:Oligodeoxyribonucleotides, Antisense; D013462:Sulfur Radioisotopes; D017868:Cyclic AMP-Dependent Protein Kinases