Efficacy, pharmacokinetics, tisssue distribution, and metabolism of the Myc-Max disruptor, 10058-F4 [Z,E]-5-[4-ethylbenzylidine]-2-thioxothiazolidin-4-one, in mice.
OBJECTIVE
c-Myc is commonly activated in many human tumors and is functionally important in cellular proliferation, differentiation, apoptosis and cell cycle progression. The activity of c-Myc requires noncovalent interaction with its client protein Max. In vitro studies indicate the thioxothiazolidinone, 10058-F4, inhibits c-Myc/Max dimerization. In this study, we report the efficacy, pharmacokinetics and metabolism of this novel protein-protein disruptor in mice.


METHODS
SCID mice bearing DU145 or PC-3 human prostate cancer xenografts were treated with either 20 or 30 mg/kg 10058-F4 on a qdx5 schedule for 2 weeks for efficacy studies. For pharmacokinetics and metabolism studies, mice bearing PC-3 or DU145 xenografts were treated with 20 mg/kg of 10058-F4 i.v. Plasma and tissues were collected 5-1440 min after dosing. The concentration of 10058-F4 in plasma and tissues was determined by HPLC, and metabolites were characterized by LC-MS/MS.


RESULTS
Following a single iv dose, peak plasma 10058-F4 concentrations of approximately 300 muM were seen at 5 min and declined to below the detection limit at 360 min. Plasma concentration versus time data were best approximated by a two-compartment, open, linear model. The highest tissue concentrations of 10058-F4 were found in fat, lung, liver, and kidney. Peak tumor concentrations of 10058-F4 were at least tenfold lower than peak plasma concentrations. Eight metabolites of 10058-F4 were identified in plasma, liver, and kidney. The terminal half-life of 10058-F4 was approximately 1 h, and the volume of distribution was >200 ml/kg. No significant inhibition of tumor growth was seen after i.v. treatment of mice with either 20 or 30 mg/kg 10058-F4.


CONCLUSIONS
The lack of significant antitumor activity of 10058-F4 in tumor-bearing mice may have resulted from its rapid metabolism and low concentration in tumors.
Hillman Cancer Center, The University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA.
Jianxia
J
Guo
Robert A
RA
Parise
Erin
E
Joseph
Merrill J
MJ
Egorin
John S
JS
Lazo
Edward V
EV
Prochownik
Julie L
JL
Eiseman
D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D002853:Chromatography, Liquid; D019281:Dimerization; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013844:Thiazoles / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D014018:Tissue Distribution; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
C524814:5-(4-ethylbenzylidene)-2-thioxothiazolidin-4-one; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D016271:Proto-Oncogene Proteins c-myc; D013844:Thiazoles; C068422:Max protein, mouse