Combination of the aptamer AS1411 with paclitaxel or Ara-C produces synergistic inhibition of cancer cell growth

4818 AS1411 is the first nucleic acid aptamer to be tested as a treatment for cancer. AS1411 is a 26-base unmodified phosphodiester-based guanosine rich oligonucleotide (GRO), which, as a dimer, forms a quartet structure resistant to serum nucleases. It is postulated to exert anti-cancer activity by binding to cell surface nucleolin; this then results in S-phase cell cycle arrest and apoptosis. In a Phase I dose-escalation trial promising signs of anticancer activity were reported in renal cancer patients (9 of 12 patients showed clinical benefit (stable disease, partial or complete response)) and the drug produced no serious adverse events at any dose tested (up to 2 cycles of 7-day infusions of 40 mg/kg/day). The aim of these studies was to evaluate the potential of combining AS1411 with various traditional cytotoxic chemotherapeutics, using in vitro cancer cell lines. Initially AS1411 was shown to induce cell killing of a broad range of human cancer cell lines, derived from both hematologic and solid cancers, typically requiring concentrations of around 5μM to cause 50% cell kill. For combination studies, A549 human non-small cell lung cancer cells were incubated with a fixed concentration of 3μM of AS1411(a concentration that did not cause growth inhibition when used alone) for 6 days with varying concentrations of the cytotoxic agents (cisplatin, paclitaxel, gemcitabine, Ara-C or 5-fluorouracil) added on day 3. Using combination index analysis, AS1411 demonstrated synergistic growth inhibition when used with either paclitaxel or Ara-C. Further work has given insights into the mechanism of action of AS1411 and will be presented. These data, alongside the general lack of toxicities observed thus far in the clinic with AS1411, attest to the promise of conducting combination studies in man with AS1411, especially with paclitaxel and Ara-C.