Abstract
UCN-01 (7-hydroxystaurosporine; NSC 638850) is a protein kinase antagonist selected for clinical trial based in part on evidence of efficacy in a preclinical renal carcinoma xenograft model. Schedule studies and in vitro studies suggested that a 72-h continuous infusion would be appropriate. In rats and dogs, maximum tolerated doses produced peak plasma concentrations of approximately 0.2–0.3 μM. However, concentrations 10-fold greater are well tolerated in humans, and the compound has a markedly prolonged T1/2. Specific binding to human α1-acidic glyco-protein has been demonstrated. These findings reinforce the need to consider actual clinical pharmacology data in “real time” with phase I studies.
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References
Akinaga S, Gomi K, Morimoto M, Tamaoki T, Okabe M (1991) Antitumor activity of UCN-01, a selective inhibitor of protein kinase C, in murine and tumor models. Cancer Res 51:4888
Akiyama T, Yoshida T, Tetsuya T, Shimizu M, Miszukami T, Okabe M, Akinaga S (1997) G1 phase accumulation induced by UCN-01 is associated with dephosphorylation of Rb and CDK2 proteins as well as induction of CDK inhibitor p21/Cipl/WAFl/ Sdi1 in p53-mutated human epidermoid carcinoma A431 cells. Cancer Res 57:1495
Bunch RT, Eastman A (1996) Enhancement of cisplatin-induced cytotoxicity by 7-hydroxystaurosporine (UCN-01), a new G2- checkpoint inhibitor. Clin Cancer Res 2:791
Bunch RT, Eastman A (1997) 7-hydroxystaurosporine (UCN-01) causes redistribution of proliferating cell nuclear antigen and abrogates cisplatin-induced S-phase arrest in Chinese hamster ovary cells. Cell Growth Differ 7:779
Hill DL, Tillery KF, Rose LM, Posey CF (1994) Disposition in mice of 7-hydroxystaurosporine, a protein kinase inhibitor with antitumor activity. Cancer Chemother Pharmacol 35:89
Kremer JMH, Wilting J, Janssen LHM (1988) Drug binding to human alpha-1-acid glycoprotein in health and disease. Pharmacol Rev 40:1
Plowman J, Dykes DJ, Hollingshead M, Simpson-Herren L, Alley MC (1997) Human tumor xenograft models in NCI drug development. In Teicher B (ed) Anticancer drug development guide. Humana, Totowa, NJ, p 101
Seynaeve CM, Stetler-Stevenson M, Sebers S, Kaur G, Sausville EA, Worland PJ (1993) Cell cycle arrest and growth inhibition by the protein kinase antagonist UCN-01 in human breast carcinoma cells. Cancer Res 53:2081
Seynaeve CM, Kazanietz MG, Blumberg PM, Sausville E, Worland P (1994) Differential inhibition of protein kinase C isozymes by UCN-01, a staurosporine analogue. Mol Pharmacol 45:1207
Takahashi I, Kobayashi E, Nakano H, Murakata C, Saitoh H, Suzuki K, Tamaoki T (1990) Potent selective inhibition of 7-O-methyl-UCN-01 against protein kinase C. J Pharmacol Exp Ther 255:1218
Tomaszewski JE, Smith AC (1997) Safety testing of antitumor agents. In Sipes IG, Gandolf AJ, McQueen CA (eds) Comprehensive toxicology, vol 2. Pergamon, New York, p 299
Wang Q, Worland PJ, Clark JL, Carlson, BA, Sausville EA (1995) Apoptosis in 7-hydroxy-staurosporine-treated T lymphoblasts correlates with activation of cyclin-dependent kinases 1 and 2. Cell Growth Differ 6:927
Wang Q, Fan S, Eastman A, Worland PJ, Sausville EA, O’Connor PM (1996) UCN-01: a potent abrogator of G2 checkpoint function in cancer cells with disrupted p53. J Natl Cancer Inst 88:956
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Work presented at the 13th Bristol-Myers Squibb Nagoya International Cancer Treatment Symposium, “Strategic Cross Talk between Major Oncology Groups/Clinical Pharmacology in Cancer Chemotherapy,” 17–18 October 1997, Nagoya, Japan
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Sausville, E.A., Lush, R.D., Headlee, D. et al. Clinical pharmacology of UCN-01: Initial observations and comparison to preclinical models. Cancer Chemother Pharmacol 42 (Suppl 1), S54–S59 (1998). https://doi.org/10.1007/s002800051080
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DOI: https://doi.org/10.1007/s002800051080