TY - JOUR
T1 - Anti-tumor activity and mechanism of action for a cyanoaziridine- derivative, AMP423
AU - Dorr, Robert T.
AU - Wisner, Lee
AU - Samulitis, Betty K.
AU - Landowski, Terry H.
AU - Remers, William A.
N1 - Funding Information:
Acknowledgments This study is supported in part by grants CA-017094, CA-115626, and CA-023074 from the National Cancer Institute, National Institutes of Health, Bethesda, MD, U.S.A. We thank the University of Arizona Chemical Synthesis Facility, and the University of Arizona Cancer Center Flow Cytometry Core Service, Experimental Mouse Shared Service, and the Biostatistical Core Service for their expertise.
PY - 2012/4
Y1 - 2012/4
N2 - 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.
AB - 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.
KW - AMP423
KW - Cyanoaziridine
KW - Imexon
KW - Preclinical
KW - Pro-oxidant
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U2 - 10.1007/s00280-011-1784-8
DO - 10.1007/s00280-011-1784-8
M3 - Article
C2 - 22186884
AN - SCOPUS:84859802410
VL - 69
SP - 1039
EP - 1049
JO - Cancer Chemotherapy and Pharmacology
JF - Cancer Chemotherapy and Pharmacology
SN - 0344-5704
IS - 4
ER -