Activation-induced apoptosis of peripheral lymphocytes treated with 7-hydroxystaurosporine, UCN-01.
7-hydroxystaurosporine (UCN-01) is a new anticancer agent which exerts an inhibitory effect on cell cycle check points and is currently under phase I clinical trials in US and Japan. Preliminary clinical data indicated that UCN-01 remained in plasma at high concentrations for long periods of time. This unavoidable high plasma drug exposure is likely to lead to hematological toxicities in patients. In the present study, cultured human peripheral blood lymphocytes (PBLs) were used to evaluate the possible hematological toxicities of UCN-01 treatment. UCN-01 induces apoptosis, and the induction of apoptosis-related surface markers were also examined to investigate the involvement of these molecules in UCN-01-induced apoptosis in PBLs. In vitro viability of PBLs was decreased by high dose of UCN-01 (25 microM, 3-day exposure). 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 annexin 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 microM 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, was induced. Con A-stimulated PBLs were more sensitive to UCN-01-induced apoptosis than 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 treated with UCN-01 at high doses.
Fukumoto
H
H
Pharmacology Division, National Cancer Center Research Institute, Tokyo, Japan.
Tamura
T
T
Kamiya
Y
Y
Usuda
J
J
Suzuki
T
T
Kanzawa
F
F
Kuh
H J
HJ
Ohe
Y
Y
Saijo
N
N
Nishio
K
K
D000470:Alkaloids / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003470:Culture Media; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects*; D008214:Lymphocytes / Q000187:drug effects*; D015375:Receptors, Interleukin-2 / Q000187:drug effects / Q000378:metabolism; D019311:Staurosporine / Q000031:analogs & derivatives; D013997:Time Factors; D019014:fas Receptor / Q000096:biosynthesis
D000470:Alkaloids; D000970:Antineoplastic Agents; D003470:Culture Media; D015375:Receptors, Interleukin-2; D019014:fas Receptor; C054852:7-hydroxystaurosporine; D019311:Staurosporine