Protein kinase C inhibitors.
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.
Swannie
Helen C
HC
CRC Department of Medical Oncology, Royal Marsden Hospital, Sutton, Surrey, UK SM2 5NG. hswannie@icr.ac.uk
Kaye
Stanley B
SB
D000470:Alkaloids / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D017209:Apoptosis; D054713:Bryostatins; D002986:Clinical Trials as Topic; D018432:Drug Resistance, Multiple; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity; D006801:Humans; D007783:Lactones / Q000737:chemistry / Q000494:pharmacology; D018942:Macrolides; D015394:Molecular Structure; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D012107:Research Design; D019311:Staurosporine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D013873:Thionucleotides / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000470:Alkaloids; D000970:Antineoplastic Agents; D054713:Bryostatins; D004791:Enzyme Inhibitors; D007783:Lactones; D018942:Macrolides; D020319:Oligodeoxyribonucleotides, Antisense; D013873:Thionucleotides; C108494:ISIS 3521; C046785:bryostatin 1; C054852:7-hydroxystaurosporine; D011493:Protein Kinase C; D019311:Staurosporine; C059539:midostaurin