Cancer Cell Kill, In Vivo Biodistribution And Antitumor Properties Of As1411, A G-Rich Oligonucleotide Aptamer

Proc Amer Assoc Cancer Res, Volume 47, 2006 4713 AS1411 (formerly AGRO100) is a 26 mer unmodified guanosine rich oligonucleotide (GRO) that has been shown to bind as an aptamer to cell surface nucleolin and induce S-phase cell cycle arrest. AS1411 is the first nucleic acid aptamer to be used systemically for the treatment of cancer. In an initial Phase I trial involving 17 patients at the Brown Cancer Center, Louisville, promising signs of anticancer efficacy have been reported, especially in renal cancer patients, at doses causing no significant adverse effects (up to 10mg/kg/day given over 7 days). The aim of these studies was to further define the preclinical pharmacological properties of AS1411 in order to guide clinical dosing and scheduling and identify possible sensitive tumor types. AS1411 induced kill of a broad range of human cancer cell lines, derived from both hematological and solid cancers, typically requiring a 4-day exposure to concentrations of around 5μM. Biodistribution studies used intravenously administered tritiated AS1411 (1, 10 and 25 mg/kg) and mice bearing subcutaneous lung (A549) or renal (A498) cancer human xenografts. Results showed that AS1411 was taken up preferentially in xenografted tumors of renal and, to a lesser extent, lung; tumor to blood ratios were typically 3-5 and were maintained up to 4 days post dosing. Across the 1 to 25mg/kg dose-range studied approximately linear pharmacokinetics were obtained between dose administered and both plasma and tumor drug levels. Significant levels of AS1411 were also detected in the colon and small intestine although to date, in rodents, dogs and patients, no gastrointestinal related toxicities have been observed. Efficacy determinations (using AS1411 given iv daily for 5 days at doses of 5, 10, 40 mg/kg) are ongoing in mice bearing A549 and A498 xenografts. The Phase I study has now re-opened to allow further dose escalation in patients with renal cancer and NSCLC.