HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:
Sign In to gain access to subscriptions and/or personal tools.

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Request Reprints Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (29) Citing Articles via Google Scholar Google Scholar Articles by Fuse, E. Articles by Figg, W. D. Search for Related Content PubMed PubMed Citation Articles by Fuse, E. Articles by Figg, W. D. Social Bookmarking                   What's this?

Review of UCN-01 Development: A Lesson in the Importance of Clinical Pharmacology

From the Clinical Pharmacology Research Core, National Cancer Institute, Bethesda, Maryland (Dr Fuse, Dr Sparreboom, Dr Sausville, Dr Figg), and Pharmacokinetic Research Laboratories, Pharmaceutical Research Institute, Kyowa Hakko Kogyo Co, Shizuoka, Japan (Dr Fuse, Dr Kuwabara).

UCN-01 is a protein kinase inhibitor under development as a novel anticancer drug. The initial pharmacologic features in patients were not predicted from preclinical experiments. The distribution volume and the systemic clearance were much lower than those in experimental animals (mice, rats, and dogs), and the elimination half-life was unusually long (>200 hours). The unbound fraction in human plasma was also much smaller than that in dogs, rats and mice, as was the binding of UCN-01 to human alpha-1 acid glycoprotein much stronger than that to human serum albumin or human -globulin. The association constants for alpha-1 acid glycoprotein and human plasma were approximately 8 x 10⁸(mol/L)^-1, indicating extremely high affinity. In this review article, the authors discuss the pharmacologic features of UCN-01 across species and provide a perspective on how this information could be applied prospectively to the future development of this agent.

Key Words: UCN-01 • drug development • anticancer drug • pharmacology

Address for reprints: William D. Figg, PharmD, Clinical Pharmacology Research Core, National Cancer Institute, 9000 Rockville Pike, Bethesda, MD 20892.

CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				Y. Dai, S. Chen, X.-Y. Pei, J. A. Almenara, L. B. Kramer, C. A. Venditti, P. Dent, and S. Grant Interruption of the Ras/MEK/ERK signaling cascade enhances Chk1 inhibitor-induced DNA damage in vitro and in vivo in human multiple myeloma cells Blood, September 15, 2008; 112(6): 2439 - 2449. [Abstract] [Full Text] [PDF]

				H. Hamed, W. Hawkins, C. Mitchell, D. Gilfor, G. Zhang, X.-Y. Pei, Y. Dai, M. P. Hagan, J. D. Roberts, A. Yacoub, et al. Transient exposure of carcinoma cells to RAS/MEK inhibitors and UCN-01 causes cell death in vitro and in vivo Mol. Cancer Ther., March 1, 2008; 7(3): 616 - 629. [Abstract] [Full Text] [PDF]

				Y. Dai, P. Khanna, S. Chen, X.-Y. Pei, P. Dent, and S. Grant Statins synergistically potentiate 7-hydroxystaurosporine (UCN-01) lethality in human leukemia and myeloma cells by disrupting Ras farnesylation and activation Blood, May 15, 2007; 109(10): 4415 - 4423. [Abstract] [Full Text] [PDF]