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Pharmacology and antitumor activity of a quinolinedione Cdc25 phosphatase inhibitor DA3003-1 (NSC 663284).

Guo, Jianxia and Parise, Robert A and Joseph, Erin and Lan, Jing and Pan, Su-Shu and Joo, Beomjun and Egorin, Merrill J and Wipf, Peter and Lazo, John S and Eiseman, Julie L (2007) Pharmacology and antitumor activity of a quinolinedione Cdc25 phosphatase inhibitor DA3003-1 (NSC 663284). Anticancer Res, 27 (5A). 3067 - 3073. ISSN 0250-7005

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Abstract

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.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Guo, Jianxia
Parise, Robert A
Joseph, Erin
Lan, Jing
Pan, Su-Shu
Joo, Beomjun
Egorin, Merrill J
Wipf, Peterpwipf@pitt.eduPWIPF
Lazo, John S
Eiseman, Julie L
Date: September 2007
Date Type: Publication
Journal or Publication Title: Anticancer Res
Volume: 27
Number: 5A
Page Range: 3067 - 3073
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Refereed: Yes
Uncontrolled Keywords: Animals, Antineoplastic Agents, Cell Line, Tumor, Colonic Neoplasms, Enzyme Inhibitors, Female, Glutathione, Glutathione Transferase, HT29 Cells, Humans, Mice, Mice, Inbred BALB C, Mice, SCID, Quinolones, Quinones, Xenograft Model Antitumor Assays, cdc25 Phosphatases
ISSN: 0250-7005
Funders: NCATS NIH HHS (UL1 TR000005), NCI NIH HHS (CA78039), NCI NIH HHS (P30CA47904-14)
MeSH Headings: Animals; Antineoplastic Agents--blood; Antineoplastic Agents--pharmacokinetics; Antineoplastic Agents--pharmacology; Antineoplastic Agents--toxicity; 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; Mice; Mice, Inbred BALB C; Mice, SCID; Quinolones--blood; Quinolones--pharmacokinetics; Quinolones--pharmacology; Quinolones--toxicity; Quinones--blood; Quinones--pharmacokinetics; Quinones--pharmacology; Quinones--toxicity; Xenograft Model Antitumor Assays; cdc25 Phosphatases--antagonists & inhibitors
PubMed ID: 17970046
Date Deposited: 07 Aug 2013 15:44
Last Modified: 13 Oct 2017 23:56
URI: http://d-scholarship.pitt.edu/id/eprint/19425

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