Aminoflavone
Mechanism of Action and Preclinical Development
AFP-464, a lysyl pro-drug of aminoflavone (AF), is synthesized to improve the aqueous solubility of the parent compound AF. AFP-464 undergoes rapid conversion to AF in plasma by nonspecific plasma esterases. AF is an investigational anticancer agent with a unique pattern of growth inhibitory activity in the NCI 60 tumor cell line screen (COMPARE analysis;
http://www.dtp.nci.nih.gov), suggesting a novel mechanism of action. Human tumor cell lines that exhibited particular sensitivity to AF included those of breast and renal origin. In vivo antitumor activity of AF was demonstrated in several xenograft studies in mice bearing A-498, CaKi-1 renal and MCF-7 breast cancer.
Previous studies with human breast and renal cancer cell lines showed that AF induced CYP1A1/1A2 and CYP1B1 protein expression and was converted to metabolites that were covalently bound to DNA. This resulted in phosphorylation of p53 with induction of the p53 downstream target p21
Waf1/Cip1 and apotosis.
Clinical Development
Two Phase I studies with AFP-464 are currently enrolling in the United States, sponsored by the National Cancer Institute, at the Mayo Clinic, University of Maryland, and Wayne State University. These studies evaluate AFP-464 in patients with Advanced Solid Tumors. For more information on these trials, please use the link below:
ClinicalTrials.gov:
A Phase I study with AFP-464 is currently enrolling in Europe. This study evaluates AFP-464 in patients with Advanced Solid Tumors. The trials is expected to enroll up to 35 patients across two research centers in Europe, with Dr. Ahmad Awada at the Jules Bordet Institute, Brussels, Belgium and Dr. Jean Charles Soria at the Institut Gustave-Roussy Villejuif, France.
Following completion of these trials, Phase II studies of AFP-464 will commence.
Publications
- Kuffel MJ, Schroeder JC, Pobst LJ, et al., Activation of the antitumor agent aminoflavone (NSC 686288) is mediated by induction of tumor cell cytochrome P450 1A1/1A2. Mol Pharmacol 2002:62:143-153.
- Loaiza-Perez AI, Kenney S, Boswell J, et al., Sensitivity of renal cell carcinoma to aminoflavone: Role of CYP1A1. The Journal of Urology 2004:171:1688-1697.
- Loaiza-Perez AI, Kenney S, Boswell J, et al., Aryl hydrocarbon receptor activation of an antitumor aminoflavone: Basis of selective toxicity for MCF-7 breast tumor cells. Mol Cancer Therapeutics 2004:3(6):715-725.
- Meng L, Kohlhagen G, Liao Z, et al., DNA-protein cross-links and replication-dependent histone H2AX phosphorylation induced by aminoflavone (NSC 686288), a novel anticancer agent active against human breast cancer cells. Cancer Res 2005:65(12):5337-43.
- Pobst LJ, Ames MM, et al., CYP1A1 activation of aminoflavone leads to DNA damage in human tumor cell lines. Cancer Chemother Pharmacol 2005.
