ANTICANCER CYTODIFFERENTIATION

DESCRIPTION (Investigator's Abstract): This application is aimed at further developing a new group of cytodifferentiating agents that are useful in the treatment of cancer and learning how they work.In a collaboration with Paul Marks and Richard Rifkind of the Sloan-Kettering Institute for Cancer Research that extends over the past 15 years, the investigators have developed novel compounds that act as effective inducers of differentiation in cancer cells, of murine erythroleukemia and also of human leukemia and colon cancer, and other cancer cell types in vitro. In addition, the earliest one of the investigators' compounds has been promising in Phase I and Phase II clinical trials. The investigators have compounds that show general effects and others that are specific either for mouse or for human cells. The investigators' new compound are more potent by about 1,000-fold, and those tested show low toxicity in animal studies. The investigators now want to design even more effective compounds and learn how they work. This latter information will be a valuable part of science in any case, and many guide the design of even better drugs. The collaborators have evidence for a variety of biological effects of the investigator's compounds, but an exciting lead is the finding that they activate a minor isozyme of protein kinase C (PKC). However, some of the investigators active compounds do not act on this enzyme and must have a different function; other data also indicates that the investigators have discovered at least two different classes of inducing agents. The investigators propose: (1) to study the PKC enzyme activation kinetically, including studies with competition by members of the different drug classes and studies with other agents that affect cytodifferentiation, to test if there is indeed strong evidence that some of the investigators compounds work by activating this enzyme. The investigators will also study species specificity and try to identify the natural substrate of this enzyme. (2) to synthesize affinity columns and photoaffinity labels based on the various drug types, to assist in the isolation and identification of their natural receptors. (3) to prepare new cytodifferentiating agents that will have better medicinal properties, building on the structure/activity relationships the investigators have developed.