Nature's Pharmaceuticals: Ancient History

Many of us tend to think of cancer as a disease of our modern age, but people throughout history recognized the uniqueness of some tumors and sought to find treatments for them. Whether physicians in ancient times were able to distinguish malignant from benign tumors is uncertain, but as early as the first century AD there are references to treatment of what we know today as cancer tumors. Modern chemotherapy has its roots deep in this past.

Colchicine

For example, as early as 300 BC Galangal (Alpinia officinarum), a root in the ginger family of plants, may have been used to treat skin cancer. According to Dioscorides, one of the most important figures in the history of Roman medicine, a plant called red clover (Trifollium pratense) may have been used in the treatment of certain forms of cancer. Red clover can aid the body to break down and to use—that is, to metabolize—certain proteins, and thus have a medical benefit. Dioscorides also recorded the ancient use of a drug made from the autumn crocus (Colchicum autumnale L.). Centuries later, in 1938, scientists investigated the autumn crocus and succeeded in isolating cholchicine, an antitumor agent.

Dioscorides

Approximately 80% of Dioscorides' Materia Medica—an encyclopedia of substances used in medicine—consists of plant medicines, with the remaining treatments divided equally between medicines from mineral and animal sources. Interestingly, this ancient division closely matches a 1976 report describing the sources of modern pharmaceuticals as follows: (a) synthetic drugs 50%; (b) plants, 25%; (c) minerals, 7%; and (d) animals, 6 %. If we consider that many modern synthetic drugs were at one time derived from plants, the percentages of Dioscorides are remarkably similar to today's.

Galen

Galen, who lived around 130 AD, was perhaps the most important ancient Greek physician. He learned anatomy in Alexandria, Egypt, which was at that time the center of medical learning. Galen became the most distinguished physician of antiquity after Hippocrates. During the Middle Ages (from AD 400 to the 1500s), the Islamic Empire, reaching from central Asia to North Africa and Spain, made significant contributions to medicine. Avicenna, an Arab physician of the late 900s and early 1000s, wrote a vast medical encyclopedia called the Canon of Medicine. Both Galen and Avicenna described what we know today as malignant tumors. Avicenna is believed to have used the term onkos (related to our word "oncology") and Galen referred to karkinos (related to our word "carcinoma").

A page from Avicenna's   Cannon of Medicine.

Historians have identified many substances found in plants that the ancients used as treatments for tumors. Such plants included the deadly nightshade, also known as belladonna. A source of several drugs, belladonna's berries can cause violent illness and even death if eaten in large quantities. Other plant sources included the kermes oak, myrrh, frankincense, nettle, and figwort. Dioscorides and Galen also described the use of the squirting cucumber (Ecballium elaterium L.), the Narcissus bulb, the castor bean (Ricinus communis L.), and spurge for ailments that are today seen as related to cancer. Scientists later investigated many of these ancient plant sources, and some were found to contain substances that have anticancer properties. This is the story common to many of the chemotherapeutic agents used today and in the past.

More recently, in 1861, Robert Bentley of Kings College, London, noted the antitumor properties of an extract of the common May apple (Podophyllum peltatum). Scientists soon had the ability to analyze such "natural products" to determine "active ingredients," the compound or compounds in the plant responsible for the observed therapeutic properties. In the 1880s, pharmacologists and chemists thought that in the May apple's active ingredient was picropodophyllum, a white crystalline solid. These researches isolated the substance and used it as an antitumor medicine. It was not until 1946 that scientists uncovered that a combination of substances found in the May apple (picropodophyllum and picropodophyllic acid, called podophyllotoxin) actually acted against tumors by preventing cells from undergoing complete cell division. Further, it was not until the 1960s that researchers were able to synthesize "structural analogues" of podophyllotoxinin the laboratory. These "structural analogues" were compounds with molecular structures similar to the original, naturally occurring substance, but having stronger powers to prevent cell division. Today, two important cancer chemotherapy drugs, etopside and teniposide, are based upon the structure of the May apple's podophyllotoxin. The story of their creation spanned more than a century and involved the contribution of dozens of researchers working at very different times and in very different places.

First the Causes, Then the Cures: The Causes

Sir John Hill

In 1801, a group of British medical and chemical investigators formed a society for the investigation of cancer. The questions that this society set out to answer were basic issues in the understanding of cancer. They asked:

• What are the diagnostic signs?
• Are there any characteristic changes in a tissue that precede the growth of cancer?
• Is cancer inherited?
• Is cancer associated with other diseases?
• Is it a localized condition?
• Is it produced by an unfavorable climate or environment?
• Is it ever susceptible of natural cure?

Over 200 years later, chemistry and medical science has found only some of the answers to these basic questions.

Sir Percival Pott in action.

Across these two centuries, developments in the search for cancer treatments relied upon the quest for a better scientific understanding of cancer itself. Environmental causes had been identified in London in the 1700s with Sir John Hill's observation that the use of snuff (a form of tobacco inhaled through the nose) caused nasal tumors. In 1775, Sir Percival Pott uncovered the first example of an "occupational cancer" among chimney sweeps. Interestingly, Pott's study was one of the earliest examples of an "epidemiological" investigation. Epidemiology, the study of the occurrence of diseases, is one of the key ways in which cancer causes are identified. Epidemiological studies often involve tracking the health of vast numbers of people and associating the presence of diseases with certain common elements in the backgrounds and lives of the afflicted.

With higher than normal cancer  rates, a chimney sweep was  unlucky, as unlucky as could be.

Associating cancers with specific substances as their cause took a major step forward in the 1910s through the work of the Japanese scientist Katsusaburo Yamigiwa. Following the old reports of cancer in chimney sweeps from the 1700s and new reports from the Danish scientist Johannes Fibiger that cancer tumors could be induced in a controlled manner within laboratory animals, Yamigaiwa set out to explore the cancer-causing effects of coal tar. He exposed the skin of rabbits to coal tar and after a year observed carcinomas on the skin, findings that he reported in 1915. Because coal tar was such a complex mixture of compounds, no specific culprit was found until 1930 when 1,2:5,6-dibenzanthracene became the first pure compound known to cause cancer. At about the same time, Francis Peyton Rous—a pathologist at Rockefeller University in New York City—found that he could cause tumors in hens by injecting them with an extract from tumors of other hens.

Francis Peyton Rous

This led Rous to propose that viruses and viral infections cause some cancers. His work was largely ignored until the 1950s and 1960s, when it received strong experimental confirmation. In 1966, 50 years after his experiments with hens and their tumors, Rous was awarded the Nobel Prize in Medicine for his work on virus-caused tumors.

Rudolf Virchow

The concentration upon cells in cancer research, and in the quest for treatments of cancer, arose following the establishment of the "cell theory" in medicine more generally. Rudolf Virchow was an important champion of the "cell theory" that indicated diseases arose at the level of cells and their processes. Virchow was both a prominent scientist and a powerful German politician. Following Virchow, scientists increasingly began to focus on cells when thinking about and trying to treat cancer. Surgical removal of cancer cells became much more effective and safe with the rise of antisepsis and anesthesia as general surgical practices. The astounding discovery of radiation from radium and X-rays in the late 1800s not only changed our understanding of the physical world, but gave rise to new methods for studying cancer's causes and treating cancers. In the late 1920s, H.J. Muller, then working at the University of Texas, Austin, discovered that radiation could produce changes, called mutations, in the chromosomes within cells. This development opened up new avenues for the study of genetics and the processes of heredity as well as the connections among genetics, heredity, and diseases like cancer. Muller was awarded the Nobel Prize for Medicine in 1946 for this path-breaking work.

First the Causes, Then the Cures: The Cures

The late 1800s and early 1900s saw an expansion in the scientific work on hormones and their effects on the body. Hormones are chemicals produced by the body's glands that act to control the body's processes. It was at this time that scientists first began to uncover a connection between hormones and cancer. The Scottish surgeon G.T. Beaston noted that breast cancers in women actually shrunk when he removed their ovaries. The ovaries produce two powerful hormones—estrogen and progesterone. In the 1930s, Charles B. Huggins, a Chicago surgeon, showed that cancer of the prostate in dogs could be stalled by castration. He found the same effect by administering the female hormone estrogen. Establishing these links has lead eventually to modern hormone therapy for cancer.

U.S. medical personnel in World War I.

Meanwhile, the deadly mustard gases used first in World War I became the topic of much research interest. Mustard gas greatly reduced the number of white blood cells in those unfortunate enough to be exposed to it. The active ingredient in the mustard gas was dichloroethylsulfide, and it was identified as the cause of the leukopenia. Dichloroethylsulfide caused leukopenia by slowing the rate at which white blood cells reproduced.

dichloroethylsulfide

Researchers eventually realized that if dichloroethylsulfide could affect the rate of white blood cell division it might also slow the rate of cancer cell division, a rate that was faster than normal. However, the studies also showed that in addition, exposure to the mustard gases caused bone marrow damage, created nausea and loss of hair, the all-to-common side effects of chemotherapy. After World War II, scientists began to synthesize analogues (compounds similar in molecular structure but with quite different properties) of the mustard gas— dichloroethylsulfide and dichloroethylamines ("nitrogen mustards") as possible chemotherapeutics. By the 1960s these new compounds—mechlorethamine, cycloposhphamide, chlorambucil, and melphalan—were part of the cancer chemotherapy arsenal, and they are still used today.

mechlorethamine	cyclophosphamide
chlorambucil	melphalan

Other chemotherapy drugs are the descendants—some are quite distant descendants—of an amazing diversity of compounds and sources. One chemotherapy agent is the descendant of the insecticide DDT, another is one of a substance found in coal tar. Still others are the descendants of a bacterium in the soil, of an evergreen shrub tea, of the Chinese tree Camptotheca acuminata, and of the tree Taxis brevifolia, the Pacific yew. The last is the best known of the "family tree" of chemotherapeutics—Taxol®—approved for treating ovarian cancer in 1994.

In a long story that began as early as 1869, physicians and researchers from all points on the globe slowly and erratically began accumulating the information necessary to identify DNA as the material central to the process of heredity, of life, and, as it turns out, to diseases like cancer. The many discoveries that marked steps along this long path are far too numerous to mention, but just after World War II a number of them arose around one particular chemical compound called folic acid.

folic acid

Scientists studying folic acid in the 1950s.

Folic acid is a vitamin that plays important roles in the life processes of cells in animals. Microbes use folic acid as a key ingredient in their growth process. These tiny animals produce their own folic acid from other compounds called "precursors." The antibiotics known as the "sulfa drugs”—the sufanilamides—combat microbes by acting upon this process of folic acid production. The antibiotic is similar in its chemical nature to one of the "precursors" and gets caught up within the microbes' attempt to produce folic acid. However, unlike the true precursor, the antibiotic does not allow the chemical reactions to continue, and thus stops the production of folic acid. Without it, the microbes cannot grow. In other animals, like humans, folic acid plays an important role in the production of both red and white blood cells and has been shown to accelerate some types of leukemias. Researchers began trying to make folic acid analogues, called folic acid antagonists, hoping to inhibit the development of leukemia by fooling the cells into taking up the modified molecule.

sulfanilamide

Just as microbes use folic acid in the chemical processes of growth, human cells use folic acid in their chemical processes for producing DNA. If the chemical factory for producing DNA could be shut down by interfering in the chemical process or "pathway"—as the sulfa drugs had done for microbes—then the process of cell division and growth could be slowed or even stopped. Such a drug for altering this chemical pathway would, thus, be a powerful tool in fighting diseases like cancer that involve cell growth and division. Thus, this folic acid story began the decades long search for the chemical pathways by which human cells form nucleic acids and through which cancer could be treated. These chemical pathways were other avenues along which chemical scientists could pursue the chemical synthesis of agents for cancer treatment. Among the pioneers in this search were Gertrude Belle Elion and George Hitchings.

In Pharmaceutical Innovation: Revolutionizing Human Health, Alexander Scriabine summarizes the major avenues in the search for chemicals to treat cancer. In roughly chronological order, they are:

• Folic Acid Antagonists — aminopterin, methotrexate, mercaptopurine
• Alkylating Agents — methchlorethamine (from mustard gas), chlorambucil, cyclophosphamide
• Antibiotics — actinomycin, idarubicin
• Antimitotic Drugs — vinblastine (from periwinkle), vincristine, etoposide, gemcitabine, capecitabine
• Sex Hormones — stilbestrol, tamoxifen
• Miscellaneous Cancer Drugs — cisplatin, paclitaxel, Intron-A, Proleukin, angiostatin, endostatin

Not only does chemotherapy have a history, but each of the anticancer agents now in use has its own history. Often many years and the work of disparate teams of researchers—and sometimes a little luck—go into developing these modern medicines used to combat the second leading cause of death in the United States—cancer.

For more information, at other Web sites...

The Chemotherapy and Pharmacology Page — from the Guide to Internet Resources for Cancer, North of England Children's Cancer Research Unit, Department of Child Health, University of Newcastle upon Tyne, UK.

Cyberbotanica: Plants and Cancer Treatments — contains information on plant-derived cancer drugs, from the University of Texas.

The Nobel Prize in Physiology or Medicine 1946 — Information on the life and work of Nobel prize winner Hermann Joseph Muller, from the Nobel Foundation.

History of Pharmacy: Robert Thom's Paintings — slide show of paintings of ancient pharmacy, including images of Dioscordes and Galen, from the Evans U.S. Army Hospital, Fort Carson MEDDAC.

Medicines by Design: The Biological Revolution in Pharmacology — from Healthier You.

The Nobel Prize in Physiology or Medicine 1966 — Information on the life and work of Nobel prize winner Peyton Rous, from the Nobel Foundation.

The Reconstructors — be the drug discoverer in this postapocalyptic sci-fi drug development game that lets you rediscover the secrets of aspirin in a future world that has lost the knowledge of modern medicine, from Rice University.

Taxol—Molecule of the Month — from Oxford University.