Pharmacology and Antitumor Activity of a Quinolinedione Cdc25 Phosphatase Inhibitor DA3003-1 (NSC 663284)

Cdc25 protein phosphatases are regulators of cyclin-dependent kinases and are often highly expressed in human malignancies. Few small molecule inhibitors of the Cdc25 phosphatase family have been identified and little is known about their disposition, metabolism or efficacy in xenograft models. In t...

Full description

Saved in:
Bibliographic Details
Published in:Anticancer research 2007-09, Vol.27 (5A), p.3067-3073
Main Authors: JIANXIA GUO, PARISE, Robert A, JOSEPH, Erin, JING LAN, PAN, Su-Shu, JOO, Beomjun, EGORIN, Merrill J, WIPF, Peter, LAZO, John S, EISEMAN, Julie L
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Agents - blood
Antineoplastic Agents - pharmacokinetics
Antineoplastic Agents - pharmacology
Antineoplastic Agents - toxicity
Biological and medical sciences
cdc25 Phosphatases - antagonists & inhibitors
Cell Line, Tumor
Colonic Neoplasms - drug therapy
Enzyme Inhibitors - blood
Enzyme Inhibitors - pharmacokinetics
Enzyme Inhibitors - pharmacology
Enzyme Inhibitors - toxicity
Female
Glutathione - metabolism
Glutathione Transferase - metabolism
HT29 Cells
Humans
Medical sciences
Mice
Mice, Inbred BALB C
Mice, SCID
Quinolones - blood
Quinolones - pharmacokinetics
Quinolones - pharmacology
Quinolones - toxicity
Quinones - blood
Quinones - pharmacokinetics
Quinones - pharmacology
Quinones - toxicity
Tumors
Xenograft Model Antitumor Assays
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Cdc25 protein phosphatases are regulators of cyclin-dependent kinases and are often highly expressed in human malignancies. Few small molecule inhibitors of the Cdc25 phosphatase family have been identified and little is known about their disposition, metabolism or efficacy in xenograft models. In this study, the efficacy, pharmacokinetics, and metabolism of a potent quinolinedione Cdc25 phosphatase inhibitor, DA3003-1, in mice was examined. DA3003-1 inhibited the growth of subcutaneous human colon HT29 xenografts in SCID mice. After a single i.v. dose of 5 mg/kg, DA3003-1 was not detectable in plasma or tissues beyond 5 min. In vitro studies showed that DA3003-1 was rapidly dechlorinated and conjugated to glutathione. Following DA3003-1 treatment of tumor-bearing SCID mice, reduced glutathione concentrations in HT29 tumor were decreased to a greater extent and remained decreased for longer than the reduced glutathione concentrations in liver and kidneys. These studies suggest that the minimal antitumor activity of DA3003-1 in mice may be due to its rapid metabolism.
ISSN:0250-7005
1791-7530