This research project is designed to carry out the isolation and structural elucidation of novel antineoplastic agents from higher plants which have confirmed activity in various cell culture (9ASK, 9KB, 9PS, human lung) and animal tumor models (P388 mouse leukemia). In addition to bioassay-directed fractionation we will employ tandem MS analysis to detect analogs of the significant lead compounds homoharringtonine (Cephalotaxus), psorospermin (Psorospermum) and podolactone C (Podocarpus species). Structural work is underway on pure actives from Cephalotaxus, Psorospermum, and Desfontainia. Fractionation is underway on Annona densicoma, Claopodium crispifolium, Psorospermum febrifugum and others with confirmed antineoplastic activity. A total of about 60 active plants are available for study. Additional leads will be developed through botanical contacts. Novel cell culture systems designed to target tubulin and specific human tumors will be employed. All novel actives will be submitted to the NCI for evaluation in the NCI animal tumor panel. This research will provide additional novel antineoplastic agents which have clinical potential. Compounds discovered will also serve as structural prototypes for analog synthesis and as biochemical tools which may aid in the elucidation of novel mechanisms of growth control.