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1.
Cancer Chemother Pharmacol ; 69(4): 1039-49, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22186884

RESUMO

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.


Assuntos
Antineoplásicos/farmacologia , Aziridinas/farmacologia , Linfoma de Células B/tratamento farmacológico , Mieloma Múltiplo/tratamento farmacológico , Naftalenos/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Aziridinas/química , Aziridinas/farmacocinética , Pontos de Checagem do Ciclo Celular , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Hexanonas/química , Hexanonas/farmacocinética , Hexanonas/farmacologia , Humanos , Linfoma de Células B/metabolismo , Masculino , Camundongos , Camundongos SCID , Mieloma Múltiplo/metabolismo , Naftalenos/química , Naftalenos/farmacocinética , Ensaios Antitumorais Modelo de Xenoenxerto
2.
J Med Chem ; 47(1): 218-23, 2004 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-14695835

RESUMO

Chemical aspects of mode of action of imexon and related cyanoaziridines were studied. These compounds do not alkylate DNA nor react with the epsilon-amino groups of l-lysine, despite the presence of an aziridine ring. They do react readily with biologically important sulfhydryl compounds to give products derived from either aziridine ring opening, interaction with the cyano group of cyanoaziridines, or opening of the iminopyrrolidone ring of imexon. The products from reactions of imexon and related cyanoaziridines with thiols are not as potent as their parent compounds against tumor cells. These results are consistent with biological studies that show that the mechanism of cytotoxicity involves thiol depletion followed by oxidative stress leading to apoptosis.


Assuntos
Antineoplásicos/química , Aziridinas/química , Hexanonas/química , Nitrilos/química , Acetilcisteína/química , Animais , Antineoplásicos/farmacologia , Aziridinas/farmacologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Hexanonas/farmacologia , Humanos , Camundongos , Nitrilos/farmacologia
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