Evidence of enhanced iron excretion during systemic phosphorothioate oligodeoxynucleotide treatment.
BACKGROUND
Phosphorothioate oligonucleotides, in general, possess properties that could be utilized in the development of therapeutic heavy metal chelators.


METHODS
Iron excretion was measured in 16 patients participating in studies to test the safety of OL(1)p53, a 20-mer phosphorothioate oligonucleotide complementary to p53 mRNA. Patients were given OL(1)p53 at doses of 0.05 to 0.25 mg/kg/h for 10 days by continuous intravenous infusion. Urine was collected during the study and analyzed for iron, copper, cadmium, and zinc.


RESULTS
We found that phosphorothioate oligonucleotides have a high affinity for iron as well as several other clinically relevant toxic metals. Analysis of patient urine following administration of OL(1)p53 reveals a 7.5-fold increase in iron excretion at low doses (0.05 mg/kg/h).


CONCLUSIONS
Phosphorothioate oligonucleotides may have therapeutic potential as heavy metal chelators. Low doses of phosphorothioate oligonucleotide facilitated the excretion of iron. Renal clearance of iron-phosphorothioate oligonucleotide complexes most likely involves secretion into proximal tubules.
University of Nebraska Medical Center, Omaha, USA.
J E
JE
Mata
M R
MR
Bishop
S R
SR
Tarantolo
C R
CR
Angel
S A
SA
Swanson
P L
PL
Iversen
D002104:Cadmium / Q000652:urine; D002614:Chelating Agents; D003300:Copper / Q000652:urine; D004305:Dose-Response Relationship, Drug; D004906:Erythrocyte Count; D006801:Humans; D007262:Infusions, Intravenous; D007501:Iron / Q000652:urine*; D007502:Iron Chelating Agents; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000652:urine; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000097:blood / Q000188:drug therapy* / Q000652:urine; D020319:Oligodeoxyribonucleotides, Antisense / Q000493:pharmacokinetics* / Q000627:therapeutic use / Q000652:urine; D012333:RNA, Messenger / Q000037:antagonists & inhibitors; D013054:Spectrophotometry, Atomic; D013873:Thionucleotides / Q000493:pharmacokinetics* / Q000627:therapeutic use / Q000652:urine; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics; D015032:Zinc / Q000652:urine
D002614:Chelating Agents; D007502:Iron Chelating Agents; D020319:Oligodeoxyribonucleotides, Antisense; D012333:RNA, Messenger; D013873:Thionucleotides; D016159:Tumor Suppressor Protein p53; D002104:Cadmium; D003300:Copper; C086760:OL(1)p53; D007501:Iron; D015032:Zinc