aprinocarsen and bryostatin-1

Protein kinase C (PKC) is a family of serine-threonine protein kinases that are involved in signal transduction pathways that regulate growth factor response, proliferation, and apoptosis. Its central role in these processes, which are closely involved in tumor initiation, progression, and response to antitumor agents, makes it an attractive therapeutic target in cancer. Despite initial activity seen in melanoma (bryostatin and UCN-01), non-Hodgkin's lymphoma (ISIS 3521, bryostatin, and UCN-01), and ovarian carcinoma (ISIS 3521 and bryostatin) in phase I studies, single-agent activity in those phase II studies reported to date has been limited. Preclinical data highlight a role for PKC in modulation of drug resistance and synergy with conventional cytotoxic drugs. A randomized phase III study of ISIS 3521 in combination with carboplatin and paclitaxel, compared with chemotherapy alone, in advanced non-small-cell lung cancer is underway. This paper reviews the rationale for using PKC inhibitors in cancer therapy, the challenges for clinical trial design, and the recent clinical experience with modulators of PKC activity.

Topics: Alkaloids; Animals; Antineoplastic Agents; Apoptosis; Bryostatins; Clinical Trials as Topic; Drug Resistance, Multiple; Enzyme Activation; Enzyme Inhibitors; Humans; Lactones; Macrolides; Molecular Structure; Oligodeoxyribonucleotides, Antisense; Protein Kinase C; Research Design; Staurosporine; Thionucleotides; Tumor Cells, Cultured

Protein kinase C (PKC) is a family of enzymes that play a ubiquitous role in intracellular signal transduction. Our understanding of the precise role of PKC has evolved considerably as a result of improved methodology and a better understanding of the signal transduction pathways. A number of primary pathways previously attributed to PKC have been re-examined and found to involve other kinases as our understanding of the PKC isozymes has evolved. PKC isozymes appear to play distinct, and in some cases opposing roles in the transduction of intracellular signals. The development of potent and selective PKC inhibitors, including isozyme-selective inhibitors, has opened new avenues for biochemical and pharmaceutical studies. The role of PKC in some of the pathways relevant to cardiovascular, peripheral microvascular, CNS, oncology, immune and infectious disease states are surveyed. A survey of the current generation of potent and selective ATP-competitive inhibitors is provided. The progress of PKC inhibitors currently in clinical development, including LY333531, ISIS 3521 (CGP 64128A), bryostatin 1, GF109203x, Ro 32-0432 and Ro 31-8220, Go 6976 and Go 7611, CPR 1006, and balanol (SPC 100840) are discussed.

Topics: Azepines; Bryostatins; Carbazoles; Enzyme Inhibitors; Humans; Hydroxybenzoates; Indoles; Lactones; Macrolides; Maleimides; Oligodeoxyribonucleotides, Antisense; Protein Kinase C; Pyrroles; Signal Transduction; Thionucleotides