Fractionation of Plants to Discover Substances to Combat Cancer
In the U.S. for the year 1998, it is estimated that about 1,228,600 persons will be diagnosed with invasive cancer, and additionally about 1 million people will contract basal or squamous cancers of the skin. Furthermore, over 1500 persons per day (or over 560,000 Americans) will die in 1998 from cancer.1 Plant natural products have had, and continue to have, an important role as medicinal and pharmaceutical agents, not only as purified isolates and extractives, but also as lead compounds for synthetic optimization.2-6 For example, if cancer chemotherapeutic agents are considered, there are now four structural classes of plantderived anticancer agents on the market in the U.S., represented by the Catharanthus (Vinca) alkaloids (vinblastine, vincristine, and vindesine), the epipodophyllotoxins (etoposide and teniposide), the taxanes (paclitaxel and docetaxel), and the camptothecin derivatives (camptotecin and irinotecan).7-10 Plant secondary metabolites also show promise for cancer chemoprevention, which has been defined as “the use of non-cytotoxic nutrients or pharmacological agents to enhance intrinsic physiological mechanisms that protect the organism against mutant clones of malignant cells.”11 There has been considerable prior work on the cancer chemopreventive effects of constituents of certain culinary herbs, fruits, spices, teas, and vegetables, in which their ability to prevent the development of cancer in laboratory animals has been demonstrated.12,13 Moreover, ellagic acid, isothiocyanates from Brassica species, and vanillin have been demonstrated mechanistically as carcinogenesis blocking (anti-initiating) agents, while curcumin, epigallocatechin gallate, limonene, and quercetin are effective carcinogenesis-suppressing (antipromotion/antiprogression) agents.14 Clinical trials as cancer chemopreventive agents on plant products such as
cucumin, genistein, and phenethyl isothiocyanate are planned under the auspices of the National Cancer Institute.15 There remains a great deal of interest in the screening of plant secondary metabolites and other natural products in modern drug discovery, not only to find potential anticancer and cancer chemopreventive agents, but also to find leads active against other disease targets.16-19
In the remaining sections of this chapter, brief details of the experimental approaches to our separate projects on the discovery of novel plant-derived cancer chemotherapeutic agents and cancer chemopreventives will be provided in turn, with emphasis of the phytochemical aspects. A number of novel bioactive plant secondary metabolites will be presented that have been isolated via activity-guided fractionation techniques in our recent work on these two projects.