Growth factor and oncogene signalling pathways as targets for rational anticancer drug development.
There is a critical need for new targets, in addition to DNA, for anticancer drug development. A recently discovered target is the intracellular signalling pathways that mediate the actions of growth factors and oncogenes on cell proliferation. Two important pathways, the myo-inositol and protein tyrosine kinase signalling pathways are reviewed. Three classes of compounds that modulate myo-inositol signalling are discussed. These are: 1) the D-3-substituted-3-deoxy-myo-inositol analogues that act as antimetabolites of myo-inositol and show selective growth inhibition of some transformed cells; 2) the alkaloid staurosporine that acts as a potent inhibitor of protein kinase C and of platelet-derived growth factor (PDGF) receptor protein tyrosine kinase activity; 3) the ether lipid analogues that block growth factor signalling at several points by acting as inhibitors of protein kinase C, phosphoinositide specific phospholipase C and inositol(1,4,5)trisphosphate-induced Ca2+ release. It is suggested that inhibition of signalling pathways may explain the growth inhibitory effects of these compounds. Other potential signalling target sites for anticancer drug development are discussed.
Powis
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Mayo Clinic and Foundation, Department of Pharmacology, Rochester, MN 55905.
Kozikowski
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D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015195:Drug Design; D006133:Growth Substances / Q000378:metabolism*; D006801:Humans; D007294:Inositol / Q000031:analogs & derivatives / Q000378:metabolism; D008055:Lipids / Q000494:pharmacology; D009857:Oncogenes / Q000187:drug effects*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D019311:Staurosporine
D000470:Alkaloids; D000970:Antineoplastic Agents; D006133:Growth Substances; D008055:Lipids; D007294:Inositol; D011505:Protein-Tyrosine Kinases; D019311:Staurosporine