Phosphorodiamidate morpholino oligomers (PMO) inhibit targeted gene expression by preventing ribosomal assembly, thereby preventing mRNA translation.
AVI-4126, a PMO targeted against c-MYC, has been extensively characterized in multiple
cancer and other disease models and is currently in human clinical trials. A phase I clinical study was conducted to address the issue of PMO bioavailability in malignant
tumors surgically excised from patients with
adenocarcinoma of prostate and breast 1 day after i.v. administration of a single dose of 90 mg
AVI-4126 PMO. The study objectives were to evaluate safety, to determine
AVI-4126 concentration in tissue samples of the
tumors, and to examine the distribution of
AVI-4126 (margin versus
tumor core). Significant concentrations of intact PMO similar to the animal models were detected in both human prostate and
breast tumor tissues with increased distribution in the
tumor core for the vascular
breast tumors. No serious adverse events (graded according to National Cancer Institute Common Toxicity Criteria) were reported. Another phase I study was conducted in normal human volunteers to assess
AVI-4126 plasma pharmacokinetics following single i.v. administration of 90 mg
AVI-4126. Data from both human studies indicated similar plasma concentration-time profile. These studies show PMO bioavailability in
tumor tissue and establish the feasibility of using PMO targeting specific genes in human
cancer clinical trials.