The first glimmering that acute leukemia, an important cause of death due to cancer in children, could respond to drug therapy came in November 1947. At that time, S. Farber and his colleagues of the Children's Cancer Research Foundation observed the first temporary remissions produced by any form of drug therapy in 10 of a group of 16 seriously ill children with acute leukemia. The remissions were characterized by shrinkage of enlarged lymph nodes, spleen, and liver, disappearance of all tumor masses, and return of the bone marrow toward normal.
Temporary recovery of leukemic children can be demonstrated by disappearance of signs and symptoms of the disease, including shrinkage of enlarged lymph nodes and spleen and return of bone marrow toward normal.
Aminopterin, the first drug, was displaced soon by a closely related, less toxic one, ameth-opterin (4-amino-Nl0-methylpteroylglutamic acid), now called methotrexate, which is one of the main drugs in use today for the treatment of leukemia and several other types of cancer. These drugs are antagonists of folic acid, a member of the B vitamin complex, and an essential metabolite with specific action in stimulating the development of red and white blood cells. The idea for the use of folic acid antagonists for controlling the proliferation of abnormal white blood cells in leukemic children was suggested by Dr. Farber's observation that folic acid stimulated the acute leukemic process. At Dr. Farber's request, a number of folic acid antagonists were supplied or synthesized by research chemists of the Lederle Laboratories Division and the Calco Chemical Division of the American Cyanamid Company, under the leadership of Y. Subbarow.
The availability of hormonal compounds for the treatment of acute leukemia stemmed from studies in the early 1940's showing the depressing effect of pituitary adrenocorticotropic hormone (ACTH) on normal lymphoid tissue. In 1949 and 1950, ACTH and hormonal compounds of the corticosteroid type, such as cortisone, were described as effective against acute leukemia, chronic leukemia, lymphosarcoma, and Hodgkin's disease.
It was obvious that close working relationships were essential among clinicians, chemists, pharmacologists, and biologists for the synthesis and testing of compounds with molecular structures designed to attack the vital components of cancer cells while sparing normal cells. Another such collaborative research effort by clinicians and laboratory scientists led to the identification of a third effective antileukemic drug. In 1952, G. H. Hitchings and his coworkers at Wellcome Research Laboratories, who for 10 years had been interested in the nucleic acids, the large chemical molecules now known to be the basic substances of life and growth, reported the synthesis of 6-mercapto-purine. This was an antagonist for the purine portion of the molecule of the nucleic acids.
The agent was tested extensively against transplanted mouse tumors and its pharmacology studied to determine toxic effects and dosage schedules first in animals and then cautiously in patients with far advanced cancer. In 1953, J. H. Burchenal and his colleagues of the Sloan-Kettering Institute published the results of the first clinical trials, showing that 6-mercaptopurine produced remissions in patients with acute leukemia, including some resistant to methotrexate. The drug had good activity in acute lymphocytic leukemia of childhood, and some activity in acute myelocytic leukemia, the type that occurs most often in adults; over the years it has become part of the standard therapy of both diseases.
The early 1950's were crucial years in shaping the future patterns of cancer chemotherapy research. A few drugs had become available that were capable of producing dramatic but temporary remissions, principally in the leukemias and lymphomas in man; even more dramatic effects occurred in animals. Several animal tumors had been found that were useful for screening chemical substances to permit predictions of their therapeutic effectiveness in patients. A few institutions, such as the Sloan-Kettering Institute under C. P. Rhoads, in New York, and Children's Cancer Research Foundation under Dr. Farber, in Boston, had begun to be identified as clinical chemotherapy centers in which the activity of the newly discovered drugs was tested in patients with far advanced disease. Agreement was universal among the small number of widely scattered investigators, however, that the problem of curative drug treatment of cancer was too complex to be pursued effectively by individual scientists or institutions without some degree of coordination of efforts.
Following several years of intensive reviews and evaluations by scientists, public groups, the National Advisory Cancer Council, and Congressional Appropriations Committees, in 1955 the National Cancer Institute began to lay the groundwork for a broadly based, voluntary, cooperative national chemotherapy program. Its major objective was to organize a drug development activity that would procure drugs, evaluate them for anticancer activity in animals, perform necessary preclinical studies, and finally evaluate promising ones in the clinic.