Author: Liu, Ying ; Zhang, Jihong ; Luo, Ying ; Wang, Yuling ; Yang, Yan ; Cheng, Xi ; Shi, Dongfang ; Stevens, Malcolm F. G. ; Tang, Tao ; Bradshaw, Tracey D.

AbstractStomach cancer is the fourth most common cancer worldwide. Identification of novel molecular therapeutic targets and development of novel treatments are critical. Against a panel of gastric carcinoma cell lines, the activity of 2‐(4‐amino‐3‐methylphenyl)‐5‐fluorobenzothiazole (5F 203) was investigated. Adopting RT‐PCR, Western blot and immunohistochemical techniques, we sought to determine molecular pharmacodynamic (PD) markers of sensitivity and investigate arylhydrocarbon (AhR) receptor‐mediated signal transduction activation by 5F 203. Potent (IC50 ≤ 0.09 μmol/L), selective (>250‐fold) in vitro antitumour activity was observed in MKN‐45 and AGS carcinoma cells. Exposure of MKN‐45 cells to 5F 203 triggered cytosolic AhR translocation to nuclei, inducing CYP1A1 (>50‐fold) and CYP2W1 (~20‐fold) transcription and protein (CYP1A1 and CYP2W1) expression. G2/M arrest and γH2AX expression preceded apoptosis, evidenced by PARP cleavage. In vivo, significant (P < .01) 5F 203 efficacy was observed against MKN‐45 and AGS xenografts. In mice‐bearing 5F 203‐sensitive MKN‐45 and 5F 203‐insensitive BGC‐823 tumours in opposite flanks, CYP1A1, CYP2W1 and γH2AX protein in MKN‐45 tumours only following treatment of mice with 5F 203 (5 mg/kg) revealed PD biomarkers of sensitivity. 5F 203 evokes potent, selective antitumour activity in vitro and in vivo in human gastric cancer models. It triggers AhR signal transduction, CYP‐catalysed bioactivation to electrophilic species causing lethal DNA double‐strand breaks exclusively in sensitive cells. 5F 203 represents a novel therapeutic agent with a mechanism of action distinct from current clinical drugs, exploiting novel molecular targets pertinent to gastric tumourigenesis: AhR, CYP1A1 and CYP2W1. PD markers of 5F 203 sensitivity that could guide patient selection have been identified.

01 Feb 2002·Molecular cancer therapeutics

Preclinical evaluation of amino acid prodrugs of novel antitumor 2-(4-amino-3-methylphenyl)benzothiazoles.

Article

Author: Double, John A. ; Tomaszewjski, Joseph E. ; Fichtner, Iduna ; Alley, Michael C. ; Cooper, Patricia A. ; Donohue, Susan ; Stinson, Sherman F. ; Stevens, Malcolm F. G. ; Sausville, Edward A. ; Bradshaw, Tracey D. ; Bibby, Michael C.

Novel 2-(4-aminophenyl)benzothiazoles (e.g., compounds 1 and 2) possess highly selective, potent antitumor properties in vitro and in vivo. Elucidation of the mechanism of action of this structurally simple class of compounds has occurred in parallel with selection of a candidate clinical agent. Antitumor benzothiazoles induce and are biotransformed by cytochrome P 450 1A1 to putative active, as well as inactive metabolites. Metabolic inactivation of the molecule has been thwarted by isosteric replacement of hydrogen with fluorine atoms at positions around the benzothiazole nucleus. Amino acid conjugation to the exocyclic primary amine function of 2-(4-aminophenyl)benzothiazoles has been used to overcome limitations posed by drug lipophilicity. Water soluble, chemically stable prodrugs rapidly and quantitatively revert to their parent amine in mice, rats, and dogs in vivo. Plasma concentrations of 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (2) regenerated from the lysylamide prodrug (2b), sufficient to elicit cytocidal activity against ZR-75-1 and T47D human mammary carcinoma cell lines persist > 6 h. The growth of breast (MCF-7) and ovarian (IGROV-1) xenograft tumors is significantly retarded by 2b. Manageable toxic side effects are reported from preclinically efficacious doses of 2b. Cytochrome P 450 1A1 protein expression, selectively induced in sensitive carcinoma cells, was detected in MCF-7 and IGROV-1 tumors 24 h after treatment of mice with 2b (20 mg/kg). The lysyl amide prodrug of 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole is potentially suitable for clinical evaluation.

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Indication	Highest Phase	Country/Location	Organization	Date
Breast Cancer	Preclinical	GB	The University of Nottingham	12 Jan 2006
Colonic Cancer	Preclinical	GB	The University of Nottingham	12 Jan 2006
Lung Cancer	Preclinical	GB	The University of Nottingham	12 Jan 2006

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