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 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.
Guo
Jianxia
J
Departments of Pharmacology, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, 15261, USA.
Parise
Robert A
RA
Joseph
Erin
E
Lan
Jing
J
Pan
Su-Shu
SS
Joo
Beomjun
B
Egorin
Merrill J
MJ
Wipf
Peter
P
Lazo
John S
JS
Eiseman
Julie L
JL
D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy*; D004791:Enzyme Inhibitors / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity; D005260:Female; D005978:Glutathione / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D019073:HT29 Cells; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D015363:Quinolones / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D011809:Quinones / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D023041:Xenograft Model Antitumor Assays; D020687:cdc25 Phosphatases / Q000037:antagonists & inhibitors*
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; C440614:NSC 663284; D015363:Quinolones; D011809:Quinones; D005982:Glutathione Transferase; D020687:cdc25 Phosphatases; D005978:Glutathione