Evidence of enhanced iron excretion during systemic phosphorothioate oligodeoxynucleotide treatment

Background: Phosphorothioate oligonucleotides, in general, possess properti es that could be utilized in the development of therapeutic heavy metal che lators. Methods: Iron excretion was measured in 16 patients participating i n studies to test the safety of OL(1)p53, a 20-mer phosphorothioate oligonu cleotide complementary to p53 mRNA. Patients were given OL(1)p53 at doses o f 0.05 to 0.25 mg/kg/h for 10 days by continuous intravenous infusion. Urin e was collected during the study and analyzed for iron, copper, cadmium, an d zinc. Results: We found that phosphorothioate oligonucleotides have a hig h affinity for iron as well as several other clinically relevant toxic meta ls. 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). Conclusi ons: Phosphorothioate oligonucleotides may have therapeutic potential as he avy metal chelators. Low doses of phosphorothioate oligonucleotide facilita ted the excretion of iron. Renal clearance of iron-phosphorothioate oligonu cleotide complexes most likely involves secretion into proximal tubules.