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Protein kinase C (PKC) is an enzyme family with serine/ threonlne kinase function which is involved in the transduction of signals for cell proliferation and differentiation. The important role played In processes relevant to neoplastic transformation, carclnogenesis and tumor cell invasion renders PKC a potentially suitable target for anticancer therapy. Bryostatin 1, a macrocyclic lactone Isolated from Bugula nerutlna, is a partial PKC agonist, and has shown potent antlneoplastic properties In vitro and in vivo. Staurosporlne, an alkaloid isolated from microbial sources, is one of the most potent PKC inhibitors and has shown high antiproliferative activity In vitro, but poor selectivity. Staurosporine analogs have thus been synthesized with the aim of obtaining more selective PKC Inhibition; among these, CGP 41251 has shown reduced PKC inhibitory activity, but a higher degree of selectivity when assayed for Inhibition of different klnases. Several studies indicate a role for PKC in the regulation of the multidrug resistance (MDR) phenotype, since several PKC inhibitors are able to partially reverse MDR and inhibit P-glycoprotein (p9P) phosphorylatlon. The MDR phenotype is also associated with variation in PKC isoenzyme content, in particular with PKC-α overexpression. While adequate PKC modulation might offer an attractive concept to modulate MDR, other potential mechanisms of PKC interaction with anticancer drugs exist and have been documented, such as the enhancement of chemotherapy-induced apoptosis by saflngol, a specific PKC inhibitor. Three phase I clinical trials with bryostatin have been completed so far and have shown that myalgia is the dose-limiting toxicity, while some antitumor activity is evident. Safingol is presently undergoing a phase I clinical trial in combination with doxorubicin. While no definitive data are presently available, it appears that saflngol plasma levels approach those associated with chemopotentiatlon in animals and no pharmacokinetic interaction between the two drugs exists. Drugs targeting PKC are well worth considering for clinical trials, particularly for their potential as modulators of currently available cytotoxic agents.