The long-term objective of this proposal is to discover novel, effective, and clinically relevant anticancer drugs targeted to human DNA topoisomerase II from Chinese medicinal plants. The compounds we anticipate to isolate will have unique activity against etoposide-resistant cells. Specifically, the extracts of these plants will be screened using a bioassay method which will permit a selection of the most promising plant sources for further study. This goal-oriented method includes assays of cytotoxicity in human KB cell lines resistant to topoisomerase II inhibitors for selection of plant extracts and assays for protein-linked DNA breaks (PLDB), inhibition of etoposide (VP-16)-induced PLDB and inhibition of topoisomerase activities for fractionation and isolation of desired compounds. Following the above bioassay-directed isolation of topoisomerase II inhibitors, the determination of the structure for those novel active compounds isolated will be carried out by modern physical methods including spectral and X-ray analyses. All active compounds will be submitted to the National Cancer Institute, NIH, for further in vitro cancer cell panels and in vivo xenograft evaluations.
