BLOCKING OF GLIOMA PROLIFERATION IN-VITRO AND IN-VIVO AND POTENTIATING THE EFFECTS OF BCNU AND CISPLATIN - UCN-01, A SELECTIVE PROTEIN-KINASE-C INHIBITOR

Seven-hydroxystaurosporine (UCN-01) is a derivative of the nonselectiv e protein kinase inhibitor staurosporine that exhibits significant sel ectivity for protein kinase C (PKC) in comparison to a variety of othe r intracellular kinases and appears to be well tolerated in vivo at co ncentrations sufficient to achieve effective inhibition of PKC. Becaus e recent studies have indicated that the proliferation of malignant gl iomas may result from activation of PKC-mediated pathways and, convers ely, may be inhibited by blocking PKC, the authors examined the effica cy of this agent as an inhibitor of proliferation in three established and three low-passage malignant glioma eel lines in vitro. A striking inhibition BE proliferation was produced by UCN-01 in each of the cel l lines, with a median effective concentration of 20 to 100 nM, which correlated with the median in vitro PKC inhibitory concentration of 20 to 60 nM for this agent in the U-87 and SG-388 glioma cell lines. Inh ibition-recovery studies of clonogenic activity indicated that UCN-01 had both cytostatic and cytotoxic effects on the treated cells. Prolif eration resumed after short-term (6- and 24-hour) exposures to this ag ent; in contrast, with longer exposures, recovery of proliferative act ivity was severely compromised. In addition, UCN-01 enhanced the inhib ition of glioma cell proliferation achieved with conventional chemothe rapeutic agents, exhibiting synergistic effects with cisplatin and add itive effects with 1,3-bis(2-chloroethyl)-1-nitrosourea. In vivo studi es in which UCN-01 was administered by continuous intraperitoneal infu sion in subcutaneous and intracranial intraparenchymal nude rat models demonstrated significant activity against U-87 glioma xenografts at d ose levels that were well tolerated. It is concluded that UCN-01 is an effective agent for the inhibition of glioma proliferation in vitro a nd in vivo and has potential for clinical applicability in the treatme nt of human gliomas.