UCN-01 induces cytotoxicity toward human CLL cells through a p53-independent mechanism.
OBJECTIVE
UCN-01, a novel protein kinase C inhibitor, is currently being tested in phase I clinical trials after being noted to induce apoptosis in lymphoid cell lines. We sought to study the in vitro activity of UCN-01 against human chronic lymphocytic leukemia (CLL) cells and potential mechanisms of action for inducing this cytotoxicity.


METHODS
Detailed in vitro studies were performed from tumor cells derived from patients with CLL cells following attainment of written informed consent.


RESULTS
The 50% loss of viability (LC(50)) in mononuclear cells from CLL patients (n = 10) following exposure to UCN-01 for 4 days was 0.4 microM (95% CI +/- 0.21; range 0.09-1.16). Loss of viability in human CLL cells correlated with early induction of apoptosis. Exposure of CLL cells to 0.4 and 5.0 microM of UCN-01 resulted in decreased expression of p53 protein. We therefore investigated the dependence of UCN-01 on intact p53 by exposing splenocytes from wild-type (p53(+/+)) and p53 null (p53(-/-)) mice, which demonstrated no preferential cytotoxicity when compared to the marked differential induced by F-Ara-A and radiation.


CONCLUSIONS
UCN-01 has significant in vitro activity against human CLL cells that appears to occur independent of p53 status. While demonstration of in vitro cytotoxicity does not establish in vivo efficacy, the findings described support the early introduction of UCN-01 into clinical trials for patients with B-CLL.
Byrd
J C
JC
Division of Hematology-Oncology, Walter Reed Army Medical Center, Washington, DC, USA. byrd-3@medctr.osu.edu
Shinn
C
C
Willis
C R
CR
Flinn
I W
IW
Lehman
T
T
Sausville
E
E
Lucas
D
D
Grever
M R
MR
D000470:Alkaloids / Q000633:toxicity*; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects*; D002478:Cells, Cultured; D002699:Chlorambucil / Q000633:toxicity; D018432:Drug Resistance, Multiple; D019254:Genes, bcl-2; D006801:Humans; D015847:Interleukin-4 / Q000494:pharmacology; D007700:Kinetics; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000097:blood / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011241:Prednisone / Q000633:toxicity; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D013154:Spleen / Q000166:cytology; D019311:Staurosporine / Q000031:analogs & derivatives; D013950:Thymus Gland / Q000166:cytology; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000633:toxicity
D000470:Alkaloids; D000970:Antineoplastic Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D002699:Chlorambucil; D015847:Interleukin-4; C054852:7-hydroxystaurosporine; D014740:Vidarabine; D019311:Staurosporine; C024352:fludarabine; D011241:Prednisone