Safety of Intracoronary Administration of c-myc Antisense Oligomers After Percutaneous Transluminal Coronary Angioplasty (PTCA)

Abstract

We wished to assess the clinical safety and pharmacokinetics of ascending doses of a synthetic oligodeoxynucleotide (LR-3280) administered after coronary angioplasty. Antisense oligodeoxynucleotides designed to hybridize with target messenger ribonucleic acid (mRNA) in a complementary fashion to inhibit the expression of corresponding protein also have the ability to bind to extracellular growth factors. LR-3280 has been shown to reduce c-myc expression, inhibit growth and collagen biosynthesis in human vascular cells, and reduce neointimal formation in animal models of vascular injury. After successful percutaneous transluminal coronary angioplasty (PTCA), 78 patients were randomized to receive either standard care (n = 26) or standard care and escalating doses of LR-3280 (n = 52) (doses from 1 to 24 mg), administered into target vessel through a guiding catheter. Overall safety was evaluated by clinical adverse events, laboratory tests, and electrocardiograms. Patency was evaluated by quantitative coronary angiography. There were no clinically significant differences between treated and control patients. No adverse effects of LR-3280 on the patency of dilated coronary arteries were observed. Pharmacokinetic data revealed that peak plasma concentrations of LR-3280 occurred at 1 minute over the studied dose range and rapidly decreased after approximately1 hour, with little LR-3280 detected in the urine between 0-6 hours and 12-24 hours. The intracoronary administration of LR-3280 is well tolerated at doses up to 24 mg and produces no adverse effects in dilated coronary arteries. These results provide the basis for the evaluation of local delivery of this phosphorothioate oligodeoxynucleotide for the prevention of human vasculoproliferative disease.

Prevention and regression of atopic dermatitis by ointment containing NF-kB decoy oligodeoxynucleotides in NC/Nga atopic mouse model

“…In contrast, NF-kB decoy ODN only exert local pharmacological effects for the following reasons: (1) ODN in serum were rapidly destroyed (within several hours), leading to a lack of systemic effects. 28 (2) The toxicity of systemic administration of ODN was only reported at over 100-fold higher concentration than that employed in the present study. 29 Indeed, serum IgE level was not affected by topical administration of NF-kB decoy ODN.…”

Transfection of NF-κB decoy oligodeoxynucleotide suppresses pulmonary metastasis by murine osteosarcoma

“…40,41 The intravenous injection of 'naked' NF-kB decoy ODN in an animal model showed accumulation in the kidney (30% of the dose per g tissue), but little accumulation in other organs. 42 Therefore, alternative delivery methods such as local administration, 43,44 combination use with cationic liposome as a carrier, 40 and physical stimulation by ultrasound wave 45,46 have been reported. In other series of study, we directly injected 'naked' NF-kB decoy ODN into a LM8 tumor mass and examined the biodistribution and the inhibitory effects of the decoy in a murine spontaneous pulmonary metastasis model.…”

Molecular strategy using cis-element ‘decoy’ of E2F binding site inhibits neointimal formation in porcine balloon-injured coronary artery model

“…In a phase 1 study, antisense c-myc ODN has been reported to be well-tolerated. 27 In the future, it is expected that ODN-based therapy will become a novel cardiovascular drug to treat restenosis. We have started to treat restenosis after angioplasty in human patients since April 2000, based on the present study.…”