Activation-induced apoptosis of peripheral lymphocytes treated with 7-hydroxystaurosporine, UCN-01

Citation
H. Fukumoto et al., Activation-induced apoptosis of peripheral lymphocytes treated with 7-hydroxystaurosporine, UCN-01, INV NEW DR, 17(4), 1999, pp. 335-341
Citations number
23
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Pharmacology,"Pharmacology & Toxicology
Journal title
INVESTIGATIONAL NEW DRUGS
ISSN journal
0167-6997 → ACNP
Volume
17
Issue
4
Year of publication
1999
Pages
335 - 341
Database
ISI
SICI code
0167-6997(1999)17:4<335:AAOPLT>2.0.ZU;2-2
Abstract
7-hydroxystaurosporine (UCN-01) is a new anticancer agent which exerts an i nhibitory effect on cell cycle check points and is currently under phase I clinical trials in US and Japan. Preliminary clinical data indicated that U CN-01 remained in plasma at high concentrations for long periods of time. T his unavoidable high plasma drug exposure is likely to lead to hematologica l toxicities in patients. In the present study, cultured human peripheral b lood lymphocytes (PBLs) were used to evaluate the possible hematological to xicities of UCN-01 treatment. UCN-01 induces apoptosis, and the induction o f apoptosis-related surface markers were also examined to investigate the i nvolvement of these molecules in UCN-01-induced apoptosis in PBLs. in vitro viability of PBLs was decreased by high dose of UCN-01 (25 mu M, 3-day exp osure). This effect of UCN-01 was significantly suppressed by the presence of human serum, suggesting that some specific inhibitory factor(s) in human serum may antagonize the lympholytic effect of UCN-01. The percentage of a nnexin V-positive PI-negative cells increased with exposure to UCN-01 in a time- and dose-dependent manner; by up to 30.3% after exposure to 25 mu M U CN-01 for 3 days. At the same time, the expression of both interleukin-2 re ceptor (IL-2R, CD25) and Fas (CD95), analyzed by flow cytometry, was induce d. Con A-stimulated PBLs were more sensitive to UCN-01-induced apoptosis th an non-stimulated lymphocytes and UCN-01 increased the sFas-L released into culture medium from con A-stimulated PBLs. Therefore, lymphocyte depletion mediated by activation-induced apoptosis is likely to occur in patients tr eated with UCN-01 at high doses.