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
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.