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Anti-tumor activity and mechanism of action for a cyanoaziridine-derivative, AMP423.
Cancer Chemother Pharmacol ; 69(4): 1039-49, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22186884
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(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.
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Texto completo: Disponível Coleções: Bases de dados internacionais Base de dados: MEDLINE Assunto principal: Aziridinas / Linfoma de Células B / Mieloma Múltiplo / Naftalenos / Antineoplásicos Limite: Animais / Humanos / Masculino Idioma: Inglês Revista: Cancer Chemother Pharmacol Ano de publicação: 2012 Tipo de documento: Artigo País de afiliação: Estados Unidos