Abstract
7-hydroxystaurosporine (UCN-01) is a new anticancer agentwhich exerts an inhibitory effect on cell cycle check points andis currently under phase I clinical trials in US and Japan.Preliminary clinical data indicated that UCN-01 remained inplasma at high concentrations for long periods of time. Thisunavoidable high plasma drug exposure is likely to lead tohematological toxicities in patients. In the present study,cultured human peripheral blood lymphocytes (PBLs) were used toevaluate the possible hematological toxicities of UCN-01treatment. UCN-01 induces apoptosis, and the induction ofapoptosis-related surface markers were also examined toinvestigate the involvement of these molecules in UCN-01-inducedapoptosis in PBLs. in vitroviability of PBLs wasdecreased by high dose of UCN-01 (25 μM, 3-day exposure). Thiseffect of UCN-01 was significantly suppressed by the presence ofhuman serum, suggesting that some specific inhibitory factor(s)in human serum may antagonize the lympholytic effect of UCN-01.The percentage of annexin V-positive PI-negative cells increasedwith exposure to UCN-01 in a time- and dose-dependent manner; byup to 30.3% after exposure to 25 μM UCN-01 for 3 days.At the same time, the expression of both interleukin-2 receptor(IL-2R, CD25) and Fas (CD95), analyzed by flow cytometry, wasinduced. Con A-stimulated PBLs were more sensitive toUCN-01-induced apoptosis than non-stimulated lymphocytes andUCN-01 increased the sFas-L released into culture medium from conA-stimulated PBLs. Therefore, lymphocyte depletion mediated byactivation-induced apoptosis is likely to occur in patientstreated with UCN-01 at high doses.
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Fukumoto, H., Tamura, T., Kamiya, Y. et al. Activation-Induced Apoptosis of Peripheral Lymphocytes Treated with 7-Hydroxystaurosporine, UCN-01. Invest New Drugs 17, 335–341 (1999). https://doi.org/10.1023/A:1006374118879
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DOI: https://doi.org/10.1023/A:1006374118879