Scientists collect parts of many different plants, prepare extracts, and test the extracts in relevant bioassays. If the assay responds to the extract, the researchers isolate the active compounds and testing of the chemical structure continues.
Chemistry professor David G.I. Kingston uses screens that test compounds as topoisomerase inhibitors or angiogenesis inhibitors.
A cancer cell is a mutant human cell that differs little from a normal cell. One difference is rapid growth; thus, cancer cell DNA is one target of treatment. The DNA of the rapidly multiplying cells is more exposed than the DNA of normal cells. Topoisomerases are enzymes that play an important role in DNA replication. When DNA is ready to multiply, its two strands uncoil and pull apart. Along each strand, a new strand forms to create two copies of the original. Anticancer drugs that are DNA topoisomerase inhibitors block the ability of DNA to uncoil, and thus prevent its replication.
Angiogenesis is the budding and growth of new blood vessels from existing blood vessels in response to a variety of growth factors. A blood supply is essential for solid tumor growth, so stopping angiogenesis would limit the ability of a solid tumor to grow. (There has been some excitement because angiogenesis inhibitors have killed tumors in mouse models. The National Cancer Institute cautions that chemicals can act differently in humans and many steps remain before such drugs can be evaluated in humans.)
Kingston uses yeast mutants with specific genes deleted to test for inhibitors of topoisomerase and angiogenesis. For example, one strain of yeast is unable to repair its DNA. If an extract damages the yeast DNA, the yeast dies, providing rapid, visible proof that the plant from which the extract was taken has developed a specific form of chemical warfare that researchers may be able to adapt to treat cancer.
After conducting some 14,000 assays of more than 3,300 extracts, Virginia Tech researchers identified 30 different, unique extracts that have activity and isolated 20 chemical compounds that have bioactivity. "Youíve got to kiss a lot of frogs before you find a prince," says Kingston.
Graduate student John Berger has been able to enhance the anticancer activity of one of the new compounds by the synthesis of analogs. The Virginia Tech research group is looking for novel compounds with more activity and with structures that can be easily enhanced.