Seven-hydroxystaurosporine (UCN-01) is a derivative of the nonselective
protein kinase inhibitor staurosporine that exhibits significant selectivity for
protein kinase C (PKC) in comparison to a variety of other intracellular
kinases and appears to be well tolerated in vivo at concentrations sufficient to achieve effective inhibition of PKC. Because recent studies have indicated that the proliferation of
malignant gliomas may result from activation of PKC-mediated pathways and, conversely, may be inhibited by blocking PKC, the authors examined the efficacy of this agent as an inhibitor of proliferation in three established and three low-passage
malignant glioma cell lines in vitro. A striking inhibition of proliferation was produced by
UCN-01 in each of the cell 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. Inhibition-recovery studies of clonogenic activity indicated that
UCN-01 had both
cytostatic and cytotoxic effects on the treated cells. Proliferation resumed after short-term (6- and 24-hour) exposures to this agent; in contrast, with longer exposures, recovery of proliferative activity was severely compromised. In addition,
UCN-01 enhanced the inhibition of
glioma cell proliferation achieved with conventional chemotherapeutic agents, exhibiting synergistic effects with
cisplatin and additive effects with
1,3-bis(2-chloroethyl)-1-nitrosourea. In vivo studies in which
UCN-01 was administered by continuous
intraperitoneal infusion in subcutaneous and intracranial intraparenchymal nude rat models demonstrated significant activity against U-87
glioma xenografts at dose levels that were well tolerated. It is concluded that
UCN-01 is an effective agent for the inhibition of
glioma proliferation in vitro and in vivo and has potential for clinical applicability in the treatment of human
gliomas.