Anti-tumor activity and mechanism of action for a cyanoaziridine- derivative, AMP423

Robert T. Dorr, Lee Wisner, Betty K. Samulitis, Terry H. Landowski, William A. Remers

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

Purpose: 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 50s 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.

Original languageEnglish (US)
Pages (from-to)1039-1049
Number of pages11
JournalCancer Chemotherapy And Pharmacology
Volume69
Issue number4
DOIs
StatePublished - Apr 1 2012

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Keywords

  • AMP423
  • Cyanoaziridine
  • Imexon
  • Preclinical
  • Pro-oxidant

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

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