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 language | English (US) |
|---|---|
| Pages (from-to) | 1039-1049 |
| Number of pages | 11 |
| Journal | Cancer Chemotherapy and Pharmacology |
| Volume | 69 |
| Issue number | 4 |
| DOIs | |
| State | Published - Apr 2012 |
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Keywords
- AMP423
- Cyanoaziridine
- Imexon
- Preclinical
- Pro-oxidant
ASJC Scopus subject areas
- Cancer Research
- Oncology
- Pharmacology
- Pharmacology (medical)
- Toxicology
Cite this
Anti-tumor activity and mechanism of action for a cyanoaziridine- derivative, AMP423. / Dorr, Robert T; Wisner, Lee; Samulitis, Betty K.; Landowski, Terry H; Remers, William A.
In: Cancer Chemotherapy and Pharmacology, Vol. 69, No. 4, 04.2012, p. 1039-1049.Research output: Contribution to journal › Article
}
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.
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
UR - http://www.scopus.com/inward/record.url?scp=84859802410&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84859802410&partnerID=8YFLogxK
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 -