title: Anti-tumor activity and mechanism of action for a cyanoaziridine-derivative, AMP423.
abstract: OBJECTIVE
  Preclinical studies evaluated the anti-tumor activity and mechanism of action of AMP423, a naphthyl derivative of 2-cyanoaziridine-1-carboxamide with structural similarity to the pro-oxidant anti-tumor agent imexon.
  
  
  METHODS
  The cytotoxic potency was evaluated in vitro against a variety of human cancer cell lines. Mechanism-of-action studies were performed in the human 8226/S myeloma cell line and its imexon-resistant variant, 8226/IM10. In vivo activity was evaluated against human myeloma and lymphoma xenografts in SCID mice. Pharmacokinetics and toxicology were investigated in non-tumor-bearing mice.
  
  
  RESULTS
  The 72-h IC(50)s for all cell types ranged from 2 to 36 μM, across a wide variety of human cancer cell lines. AMP423 was active in SCID mice bearing 8226/S myeloma and SU-DHL-6 B-cell lymphoma tumors, with a median tumor growth delay (T-C) of 21 days (P = 0.0002) and 5 days (P = 0.004), respectively, and a median tumor growth inhibition (T/C) of 33.3% (P = 0.03) and 82% (P = 0.01), respectively. In non-tumor-bearing mice, AMP423 was not myelosuppressive. Mechanistic studies show that AMP423's mode of cell death is a mixture of necrosis and apoptosis, with generation of reactive oxygen species, inhibition of protein synthesis, and a decrease in reduced sulfhydryl levels, but no alkylation of nucleophiles. Unlike its structural analog imexon, which causes cell cycle arrest in G(2)/M, AMP423 induces the accumulation of cells in S-phase.
  
  
  CONCLUSIONS
  AMP423 has pro-oxidant effects similar to imexon, has greater cytotoxic potency in vitro, and has anti-tumor activity in hematologic tumors in vivo.
authors.affiliation: The University of Arizona Cancer Center, College of Medicine, 1515 N Campbell Avenue, Tucson, AZ 85724-5024, USA. bdorr@azcc.arizona.edu
authors.forename: Robert T
authors.initials: RT
authors.lastname: Dorr
authors.forename: Lee
authors.initials: L
authors.lastname: Wisner
authors.forename: Betty K
authors.initials: BK
authors.lastname: Samulitis
authors.forename: Terry H
authors.initials: TH
authors.lastname: Landowski
authors.forename: William A
authors.initials: WA
authors.lastname: Remers
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001388:Aziridines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D006588:Hexanones / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism; D009281:Naphthalenes / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: C573865:AMP423; D000970:Antineoplastic Agents; D001388:Aziridines; D006588:Hexanones; D009281:Naphthalenes; C014919:4-imino-1,3-diazabicyclo(3.1.0)hexan-2-one