AS-1411, a guanosine-rich oligonucleotide aptamer targeting nucleolin for the potential treatment of cancer, including acute myeloid leukemia.
In development by Antisoma plc, AS-1411 is the first oligodeoxynucleotide aptamer to reach phase I and II clinical trials for the potential treatment of cancers, including acute myelogenous leukemia (AML). As an aptamer, AS-1411 does not appear to engage in hybridization-requiring pathways such as antisense effect, siRNA or triple helix formation. Instead, AS-1411 appears to bind to nucleolin specifically, and is subsequently internalized into the tumor cell. Nucleolin is an abundant protein, with expression that is correlated with the proliferative status of the cell: nucleolin levels are higher in tumors and actively dividing cells. Because of the multifunctional nature of nucleolin, it is probable that many secondary targets are affected following treatment with AS-1411. AS-1411 has demonstrated preclinical growth inhibition activity against a wide variety of tumor cell lines at concentrations in the micromolar range, and resulted in good efficacy in mice xenografted with tumor cells of human origin. In a phase I clinical trial in patients with advanced, refractory cancers with metastases at multiple sites, AS-1411 was safe and well tolerated; in addition, one complete response and one ongoing partial response were reported in two patients with renal cell carcinoma. A phase II trial of AS-1411 in combination with cytarabine in patients with AML demonstrated the combination to be superior to cytarabine alone. Thus, AS-1411 appears to be a promising candidate for cancer treatment in these pathologies. A greater understanding of the mechanism of action of this agent is essential to aid in future research.
Université de Lyon, Ecole Normale Supérieure de Lyon, CNRS-USR and IFR Biosciences, France.
Fabien
F
Mongelard
Philippe
P
Bouvet
D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D052157:Aptamers, Nucleotide / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D002986:Clinical Trials as Topic; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D009369:Neoplasms / Q000188:drug therapy*; D009838:Oligodeoxyribonucleotides / Q000737:chemistry / Q000627:therapeutic use*; D010750:Phosphoproteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000097796:Nucleolin
D000970:Antineoplastic Agents; D052157:Aptamers, Nucleotide; D009838:Oligodeoxyribonucleotides; D010750:Phosphoproteins; D016601:RNA-Binding Proteins; D000097796:Nucleolin; C513936:AGRO 100