Taxol

Cancer research before 1960

The discovery of penicillin and its successful production and distribution during World War II ushered in the modern age of antibiotics. The success of these new drugs convinced many that diseases could be eradicated chemically. The discovery of additional antibiotic drugs such as erythromycin and tetracycline changed mortality patterns drastically: by the 1950s deaths from infectious diseases, especially pneumonia, began to decline and heart disease and cancer became major killers. Interest in cancer research, especially chemotherapy, intensified with the increase in cancer deaths.

The history of chemotherapy is rooted in research in gas warfare conducted by the United States and Britain during World War II. That experience convinced some researchers that chemical agents could be used to destroy or control the growth of cancer cells, the core definition of chemotherapy. After the war, experiments were conducted using nitrogen mustards to fight leukemia. Much of this work was done at the Sloan-Kettering Institute for Cancer Research in New York City where many of the scientists who had worked in the Chemical Warfare Service during wartime relocated in peacetime.

About 75% of the compounds evaluated as potential cancer fighters in the early 1950s were tested at Sloan-Kettering. But the institute’s capacity could not satisfy the needs of the scientific community, and demands mounted for creation of a national cancer drug screening program. At the same time public pressure to do something about cancer increased, and it found voice in the lobbying efforts of the American Cancer Society, which agitated for increased funding for research. As a consequence, the budget of the National Cancer Institute (NCI) grew from $0.5 million in 1937, its first year, to $1.75 million in 1946 and $14 million in 1951 (ten years later the budget reached $110 million). And there was more money from the National Institutes of Health and from private sources for research grants. By the early 1950s cancer research had become well funded.

But it was not well organized. To correct deficiencies in the evaluation of potential drugs, NCI created the Cancer Chemotherapy National Service Center (CCNSC) in 1955 to act as a public screening facility using standardized procedures for compounds submitted by companies and institutions. Initially, CCNSC evaluated mostly compounds whose chemical structures were well known, such as synthetics and fermentation products. In 1960 the program began to screen extracts of natural products, both plant and animal, as complex mixtures of compounds of unknown structures. By that year CCNSC was screening 30,000 samples a year, about ten times Sloan-Kettering’s volume.

Humans have long used plants for a multitude of medical purposes. Before 1960 very few of these had been studied systematically, and even fewer had been examined for anticancer activity. While there was a great deal of folkloric knowledge about the general medicinal properties of plants, virtually nothing was known about the cytotoxic and antitumor potential of plants.

The organizer of the NCI plant program was Jonathan Hartwell, an organic chemist who in 1958 became Assistant Chief for Program Analysis Activities at CCNSC. Hartwell in a sense grew up with NCI, becoming a research fellow shortly after the Institute opened its doors. He was the perfect choice to head the plant screening project because he had wide experience in natural products chemistry, and he believed that plants had chemotherapeutic potential. Hartwell compiled a comprehensive work on the traditional use of plants to treat cancer, complete with references to the literature of the ancient Chinese, Egyptians, Greeks, and Romans.

Hartwell’s interest in what he called “cancer plants” went beyond folklore. In the early 1950s, in a study of plants known to be biologically active, NCI had investigated savin, Juniperus sabina, a small juniper bush that showed some anticancer activity. The results proved mediocre in the end, but the search was on for active conifers. To find specimens and to obtain accurate botanical information, Hartwell turned to the United States Department of Agriculture. In June 1960 NCI and the USDA agreed on a cooperative program to supply NCI with plants for anticancer screening. During the next two decades USDA botanists collected plants throughout the United States with the goal of providing a broad taxonomic cross-section of plants for screening.

Samples of plants obtained by the USDA were sent to the Wisconsin Alumni Research Foundation, which prepared the crude extracts. These in turn were sent to various laboratories for testing in a number of bioassay systems to see if they had a potential for killing cancer cells. In the initial years of the program samples were tested in one in vitro screen, KB (oral epidermoid carcinoma) cell culture, a cell line from a human cancer. They were also tested in three in vivo screens in tumors planted in laboratory mice. The in vivo screens were for S-180, a sarcoma; CA-755, an adenocarcinoma; and L1210, a lymphoid leukemia.

The crude extracts that showed potential for activity became candidates for fractionation, a process geared to isolate the active compounds. Fractionation was done at three laboratories, one of which was the newly organized Research Triangle Institute (RTI) in North Carolina which opened in 1958 and which two years later hired Monroe Wall to head its Natural Products Laboratory. Wall had been in charge of a program at the USDA’s Eastern Regional Research Laboratory that analyzed plants growing throughout the United States in the search for phyto-steroids that could serve as precursors to cortisone, which was in great demand but of limited supply at that time. A thousand extracts of plants sampled over the ten years of this project were sent to NCI to test their anticancer potential. One of them, Camptotheca acuminata, a tree native to China, demonstrated potent anticancer activity in the CA-755 assay. Work on isolating the compound responsible for this activity moved to RTI with Wall in 1960.

next | back | home