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.
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 humancancer 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 humanmyeloma and lymphoma xenografts in SCIDmice. 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 humancancer cell lines. AMP423 was active in SCIDmice 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: Katerina Dvorakova; Claire M Payne; Margaret E Tome; Margaret M Briehl; Miguel A Vasquez; Caroline N Waltmire; Amy Coon; Robert T Dorr Journal: Mol Cancer Ther Date: 2002-01 Impact factor: 6.261
Authors: Katerina Dvorakova; Claire M Payne; Terry H Landowski; Margaret E Tome; Daniel S Halperin; Robert T Dorr Journal: Anticancer Drugs Date: 2002-11 Impact factor: 2.248
Authors: M Tomasz; D Chowdary; R Lipman; S Shimotakahara; D Veiro; V Walker; G L Verdine Journal: Proc Natl Acad Sci U S A Date: 1986-09 Impact factor: 11.205