By 1955 the pace of drug discovery was accelerating. A number of new types of alkylating agents, drugs whose mechanism of action is similar to that of nitrogen mustard, had been synthesized and found temporarily active against various types of cancer. These agents included TEM (triethylene melamine), TEPA (triethylenephosphoramide), thioTEPA (tri-ethylenethiophosphoramide), busulfan, and chlorambucil. In 1957, investigators in Germany synthesized cyclophosphamide, a compound that has become one of the important drugs for the treatment of acute leukemia in children.
Also in 1957, a compound representing; an entirely new class of tumor-inhibitory agents was designed and synthesized by C. Heidel-berger of the University of Wisconsin in collaboration with R. Duschinsky of Hoffmann-LaRoche, Inc. Starting from an observation made by other investigators that certain animal tumors utilized uracil, part of the pyrimidine portion of nucleic acid, Drs. Heidelberger and Duschinsky and their coworkers reasoned that an antagonist containing an atom of fluorine in place of a hydrogen atom in the molecule might show anticancer activity. The compound, 5-fluorouracil, did have activity in a number of animal tumors. When placed into clinical trial, it was somewhat effective in patients with advanced solid tumors of the colon or rectum, stomach, and breast, although producing marked toxic reactions particularly in the gastrointestinal tract and the mouth. A related compound, 5-fluorodeoxyuridine, showed similar characteristics. Accordingly, the clinicians decided that pyrimidine analogues had definite value in the treatment of a variety of types of cancer, but that extensive studies were necessary to determine how best to use them as anticancer drugs.
One of the first pyrimidine analogues used against malignant tumors was 5-fluorouracil. It acts as an antagonist against cancer cells by blocking the cell's metabolism of uracil, part of the pyrimidine portion of nucleic acid. Observation of this reaction opened the door to a new class of anticancer drugs.
A chance observation in the laboratories of R. L. Noble of the University of Western Ontario and his colleagues led to the production in the late 1950's and early 1960's of two useful drugs from the white-flowered periwinkle plant, Vinca rosea. The group had been studying various plant extracts thought to have been used by primitive peoples, and decided to test a tea made from the leaves of a periwinkle plant of Jamaican origin that had been suggested as useful in the control of diabetes mellitus. They found the plant extracts given orally ineffective in lowering the blood sugar of experimental animals and subsequently tried injection of the extracts into the animals. Unexpectedly, many of the animals died, and further study showed that they had markedly decreased white blood cell counts and profoundly depressed bone marrows.
An extract or "tea" made from leaves of the was the source of the cancer drugs, vincristine and vinblastine.
A crystalline alkaloid, vincaleukoblastine sulfate, later named vinblastine sulfate, was prepared from the active extracts. Independently and at about the same time, a group working in the laboratories of Eli Lilly and Company under the leadership of G. H. Svoboda obtained the same compound. Preliminary clinical trials showed that the compound was sufficiently promising against several types of solid tumors, as well as Hodgkin's disease and other lymphomas, to warrant further study of its usefulness for the treatment of human cancer.
Not long afterwards, the Lilly group was successful in isolating a second alkaloid with a chemical structure similar to that of vinblastine. This compound, vincristine, prepared also as the sulfate, is today one of the main drugs for the treatment of acute leukemia of childhood and has found application in other types of malignant disease as well.