Agents which block the formation of second messengers which mediate growth factor action may be of value in cancer chemotherapy. Recently the hydrolysis of phosphatidylinositol-diphosphate (PIP2) to produce diacylglycerol (DAG) and inositol triphosphate (IP3) has been implicated in the action of a number of growth factors, including platelet derived growth factor and bombesin. We are therefore attempting to examine the chemotherapeutic effects of inhibition of this process and to develop inhibitors of various enzymes involved in PI metabolism. During this period we have completed development of a new method for the separation and measurement of inositol phosphates. This technique has revealed that the metabolism of these compounds is more complex than previously known, and involves multiple positional isomers. Further studies are needed to explore the role of these compounds in growth factor action. Our initial efforts in drug development have centered on a series of myo-inositol analogs. We have developed a structure-activity profile for the incorporation of these analogs into fraudulent PI analogs. We also examined the uptake and utilization of myo-inositol and the new analogs by cells in culture.
