Plants and Plant Products as Sources of Pharmaceuticals

by James D. McChesney, Director, Research Institute of Pharmaceutical Sciences, University of Mississippi, University, MS; M.A. Wallig, Assistant Professor, Department of Veterinary Pathobiology, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, IL; and Gordon Cragg, Chief, Natural Products Branch, Division of Cancer Treatment, National Cancer Institute, Frederick, MD.

Human survival has always depended on plants. Early humans relied heavily on plants for food, medicine, and much of their clothing and shelter. The botanical skills of these early people should not be underestimated; all of the world's major crops were already domesticated in prehistoric times. The Age of Discovery was fostered by Europeans' explorations to find more economical trade routes to the East to bring back plant-derived spices and other products. Indeed, the first permanent contacts between Europe and the Americas 500 years ago was a direct consequence of that effort.

Aside from their value as sources of food, drugs, or industrial raw materials, plants are also important to humankind in many other ways. One can hardly imagine modem society without soaps and toiletries, perfumes, condiments and spices, and similar materials, all of plant origin, which enhance our standard of living. The roles of forests and other types of natural vegetation in controlling floods and erosion, in removing carbon dioxide from the atmosphere, and in providing recreational facilities are of immeasurable worth.

An adequate food supply is, and always has been, one of humanity's most pressing needs. Paralleling our need for food is our need for treatments for ailments. The practice of medicine today is very different from that of earlier times. This is largely because modem doctors have available a wide array of medicines with specific curative effects.

However, we still lack specific curative agents for a number of important diseases. Some 800 million to 1 billion people, nearly one-fifth of the world's population, suffer from tropical diseases: malaria, schistosomiasis, leprosy, leishmaniasis, etc. In the United States, heart disease, cancer, viral diseases (for example, AIDS), antibiotic-resistant infections, and many other ailments still lack adequate treatment.

Progress toward cures of the serious diseases that still afflict humankind depends upon discovery of new chemotherapeutic agents (drugs) which can effectively treat them. The search for new drugs has traditionally involved evaluating preparations of organisms (particularly higher plants) to look for appropriate biological activity. This is followed by the purification and characterization of the substance(s) responsible for the desired activity.

Effect of Discovering Quinine

This approach to drug discovery became commonplace after the 1820 discovery of quinine as the active ingredient in the antimalarial Cinchona bark. With the discovery and utilization of quinine as a pure chemical entity (drug), the course of modem drug discovery was irreversibly altered. An analysis of the historical development of the 20 most important pharmaceuticals utilized in the United States in 1988 reveals that in each case plants contributed an essential role, supplying either the actual medicines, leads for the medicinal chemists who developed the drugs, or precursors for preparation of the final medicines.

Efforts to develop new, clinically effective pharmaceutical agents have relied primarily on one of five approaches: (1) derivatization of existing agents, (2) synthesis of compounds similar to existing agents, (3) combination therapy of existing agents with other drugs, (4) improvements of delivery of existing agents to the target site, or (5) discovery of new prototype pharmaceutical agents.

While approaches 1-4 are important and need to be continued, there is an urgent need for the development of totally new prototype agents that do not possess the same toxicities, cross resistance, or mechanism of action as existing agents. Natural products have, in the past, provided a rich source of such compounds. It is essential that the search for new drugs continue to pursue this route. The major advantage of this approach is the likelihood of identifying new prototype drugs with quite different chemical structures and mechanisms of action and, hence, lower likelihood of similar toxicities and cross-resistance. Clearly, the higher plants represent a bountiful source of new prototypic bioactive agents that must be examined.

Bioassay Is Fundamental

The fundamental element of a drug discovery program is the bioassay(s) to detect the desired biological activity. The bioassay procedure selected for searching for new prototype drugs must meet a variety of criteria. In addition to ease of operation and low-to-moderate cost, the assay must show specificity and sensitivity to minute amounts of the agent being sought. Another important requirement of the assay is its ability to serve as a guide to selecting the agents showing activity for further purification. This is especially important in the screening of substances from natural sources, since these materials are likely to be in very low concentration in very complex mixtures. Only a combination of procedures meets these demanding criteria to serve as primary screens for biological activity.

Other important program elements must be coupled to the appropriate bioassay. The probability of selection and procurement of novel sources of potential preparations must be demonstrated. Also, it must be possible to adequately purify the active materials and to determine their structure. Initially detected activity must be confirmed in subsequent trials that help define the potential clinical utility of the substance. Finally, a "portfolio" of information about the substance must be accumulated in order to make a judgment about its potential for successful development into a clinically useful agent. For example, something must be known about such factors as its general toxicity, pharmacokinetics (how drugs are absorbed and eliminated from the body), mechanism of action, and analog development (which improves the clinical usefulness of the newly discovered chemical agent).

There are continuing efforts to discover and develop cancer chemotherapeutic agents from plants. Recent results show that certain chemicals found in select plants hold exciting promise for preventing or lowering the incidence of cancer. This is a specific example of how plant-derived chemicals will continue to contribute to the well being of humankind.

Discovery and Development of New Chemotherapeutic Agents

Plants have a long history of use in the treatment of cancer, though the majority of claims made for the efficacy of such treatment must be viewed with skepticism. Cancer is likely to be poorly defined in terms of folklore and traditional medicine, making it difficult to prove a specific treatment was effective. However, the National Cancer Institute (NCI) of the U.S. Public Health Service has recognized the value of plants as sources of potential anticancer agents. In 1960, NCI initiated a systematic effort to collect and screen plants for anticancer properties in collaboration with USDA. Between 1960 and 1982, some 35,000 plants were collected by USDA in over 60 countries and screened by NCI against a range of animal tumor systems.

A large number of chemical classes of plant products have shown activity in the animal tumor screens. Several plant-derived agents are now either in regular clinical use for the treatment of cancer victims or undergoing clinical evaluation. The best known of these agents are the so-called Vinca alkaloids, vinblastine and vincristine, isolated from the Madagascar periwinkle, Catharanthus roseus. These drugs first became available in the 1960's, and are now used extensively, generally in combination with other agents, in the treatment of a wide variety of different cancer types.

With their use, long-term, disease-free survivals have been observed in the treatment of various lymphomas and leukemias, bladder cancer, and testicular cancer, and significant palliative benefits have been seen in patients with breast cancer, melanoma, and small-cell lung cancer. However, despite years of intensive research aimed at the viable synthesis of these agents, the cultivated plant is still the major source. Until recently, the pharmaceutical company Eli Lilly was their major producer, using plants mass-cultivated for this purpose in Texas. With the expiration of Lilly's patents on these agents, cultivation and production ventures have been initiated in other countries.

Two other agents in clinical use are etoposide and teniposide, semisynthetic derivatives of podophyllotoxin, a lignan isolated from the Mayapple, Podophyllum peltatum, or from Podophyllum emodii. These agents show clinical activity against small-cell lung and testicular cancers, as well as lymphomas and leukemias. The starting materials for semisynthesis of these agents are isolated mainly from the Asian species Podophyllum emodii, which grows in the wild. However, supplies of this plant are reported to be dwindling, and it is possible that cultivation will be necessary to meet the demand for these agents.

The Promise of Taxol

The most recent addition to the cancer chemotherapy armamentarium is taxol. Taxol currently is isolated from the bark of the slow-growing Pacific yew, Taxus brevifolia. Significant clinical activity has been observed against refractory ovarian cancer, and substantial activity has been reported recently in the treatment of breast cancer. The supply of taxol needed to treat people with these two cancers in the United States alone is at least 100 kilograms per year. If preliminary activity observed against other serious cancers, such as lung cancer, is confirmed, the demand could exceed 300-400 kg. per year. It is clear that the bark of the Pacific yew will never meet these escalating demands, but taxol and related compounds, which can be converted into taxol, can be isolated from the leaves of other Taxus species.

Fortunately, various cultivars of Taxus species are popular ornamental shrubs in the United States, and a number of nurseries cultivate them on a large scale. NCI, in collaboration with USDA, Zelenka Nurseries, the University of Mississippi, and the Ohio State University, has initiated a program for the large-scale harvesting, drying, and extraction of the leaves of a common Taxus cultivar. Extracts will be processed to yield taxol and related compounds. It is anticipated that this renewable source will replace the Taxus brevifolia bark source in the next few years. This will relieve the pressure on this old-growth forest species and provide an important new source of income for growers of ornamental Taxus.

Taxus species have a distinguished history, and the historical and cultural significance of these magnificent trees has been recounted in a recent book, "The Yew Tree: A Thousand Whispers," by Hal Hartzell (1991). For centuries, Yew wood was used extensively in Europe in the manufacture of the longbows which played a dominant role in English victories in famous battles such as Agincourt. It seems ironic but appropriate that the role of these legendary plants has been transformed from that of use in the manufacture of implements of war to use in the manufacture of drugs in the war on cancer.