Concepts, Mechanisms, and New Targets for Chemotherapy

This work describes interconnections between rationally designed and empirically discovered compounds. It features the route of protein kinase C inhibition. This pathway may be exploited to give potent inhibitors, such as the bryostatins, now in clinical trial. A summary is given of the current status of topoisomerase, focusing on recent clinical advances with camptothecin analogues based on connecting empiricism with concepts of drug selectivity. Modification of existing therapies based on the pursuit of leads arising from mechanistic studies is also being applied clinically on a wide scale. Greater understanding should follow from the studies of reversal of the multidrug resistant phenotype, on the use of hydroxyurea to reverse resistance mediated by extrachromosomal DNA, and on various aspects of the fluoropyrimidine pathways. Successful applications of chemotherapy to the treatment of specific diseases include the growing applications of systemic therapy using various skin malignancies. In prostate cancer, estramustine phosphate will likely play an expanding role.Taxanes are restructuring treatment regimens in breast cancer, and high-dose strategies are described with peripheral blood progenitor autografting in the treatment of ovarian and breast cancers.