The First Effective Chemotherapy for Cancer
Sulfur mustard gas had no influence on the outcome of the battle at Ypres during World War I despite the many deaths and severe injuries it inflicted. Since then, chemical weapons have been used in conflicts at least fifteen times between 1919 and 2016 - in the Iraq-Iran War, by Iraq against the Kurds, and by the Syrian government against their own citizens. The inability of poison gas to change the outcome on the battlefield is compounded by the gruesome effects it has on combatants and on civilians.
The need to manage the injured on the battlefield led to advances in surgery, transfusion medicine, emergency medicine, critical care, and trauma management. In an effort to mitigate the effects of exposure to sulfur mustard gas, research on its chemical effects on tissue resulted in rational chemical therapy for lymphoid and non-lymphoid tumors. When the Germans used artillery shells containing dichlorethylsulfide (sulfur mustard gas) in the First World War, postmortem studies on the victims showed injury (cell death) to tissues with rapid cell turnover. Since rapid cell turnover is frequently a feature of neoplastic growth, this prompted studies on the effects of mustard on cancer cell proliferation, leading to the study of rational pharmacological therapy.
James Ewing (1896-1943), a pathologist interested in cancer at Cornell Medical School, was a prime mover in establishing the American Association for Research on Cancer and the American Association for the Control of Cancer (now the American Cancer Society). He supported programs in cancer care and radiotherapy at the neighboring General Memorial Hospital which evolved into the Memorial Sloan-Kettering Cancer Center in Manhattan. Ewing argued in favor of studying the effect of mustard gas on neoplastic tissue. His views prompted Frank E. Adair (1888–1982), who had served in France during World War I and was a leading cancer surgeon with a special interest in breast cancer, and Halsey J. Bagg (1890–1947) at the Memorial Hospital to study the effects of a solution of dichlorethylsulphide (sulfur mustard) on normal skin, mouth, bladder, and rectum of rabbits and to tar-induced carcinoma of mice. Subsequently, they studied the effects of sulfur mustard on thirteen people with superficial cancers of the skin, penis, and other sites by topical application or by injection into the tumor. (1) No success resulted from these early explorations in the late 1920s and early 1930s.
At the outbreak of the World War Two, the United States Army and the Scientific Office of the British Commonwealth formed governmental structures and committed resources to support research into the biological effects of mustard gas. In the United States, the studies were under the aegis of the National Research Council’s wartime committees, which advised the Surgeon General. One was the Committee on Treatment of Gas Casualties, chaired by Milton C. Winternitz, professor of pathology and dean of the Yale School of Medicine and author of the 1920 text The Pathology of War Gas Poisoning. Winternitz argued that an effort should be made to better understand the biological effects of these profoundly injurious agents. An advisory committee to the Secretary of War, in response to these urgings, proposed that Yale University establish a center to explore the biological effects of war gases.
In 1942, this program was started through a contract executed by the United States Government with Yale University. The vesicant properties of the gases made their laboratory study difficult and hazardous. This led the Yale scientists Louis Sanford Goodman and Alfred Gilman to synthesize nitrogen mustards (not sulfur mustards) that could be studied as liquids and injected intravenously. They described the cytotoxic effects of nitrogen mustard on tissues with rapid cell turnover: the marrow, lymphocytes in lymph nodes, and gastrointestinal epithelium. The normal function of these three tissues depends on an essential population of continuously dividing cells. The effects on lymphoid tissue led to a collaboration with members of the Yale Department of Anatomy, who were working with experimental animal models of lymphoma. They injected nitrogen mustard into mice with a transplanted lymphoma and found a reduction in tumor size. Additional animal studies confirmed these initial findings, resulting in testing two nitrogen mustard compounds on human subjects with Hodgkin’s disease, other lymphomas, leukemias, and other cancers.
The first patient treated with nitrogen mustard was at New Haven Hospital. By 1943 a few humans with cancer, principally lymphoid cancers, had been studied, but the war-related tragedy in the harbor of Bari, Italy, choked with Allied ships at anchor, extended the human observations of mustard effects on highly proliferative tissue. In 1943, an unexpected Luftwaffe air attack on ships carrying fuel and other war necessities for the 15th Air Corps, recently moved from North Africa to Italy, resulted in horrific damage including the release of sulfur mustard into the atmosphere and water, leading to many casualties and deaths from this agent. The Allies had moved mustard-containing artillery shells to Italy to be prepared for retaliation if the Germans used this agent in desperation. Examination of some of the affected merchantmen and seamen confirmed the damage to the marrow, lymphatic tissues, gastrointestinal mucosa, and of course, skin and lungs. The only positive result of this horrendous tragedy was that the autopsy and medical findings, which supported the few human studies of mustards at that time, were thought to further accelerate the use of mustard compounds in cancer treatment, most notably in patients with Hodgkin’s disease. (Later, the disease was renamed Hodgkin lymphoma when it was shown that the disease originated in a mutated B lymphocyte, whereas previously the cell of origin had been in dispute, and the apostrophe was removed from eponymous designations.)
About a year after the war’s end, in April 1946, Gilman and Frederick S. Phillips published in Science a description of the chemistry of the mustard compounds and their tissue effects. They commented on their nucleotoxic effects and indicated that the tissue effects were unlike any other chemical agent but closely simulated those of X-radiation (radiomimetic). They described the results of the first six patients treated and indicated that there were results from treating approximately 150 patients, but the data were still under wartime secrecy restrictions. The most dramatic responses were seen in Hodgkin’s disease, not in lymphoma or acute or chronic leukemia.
In 1946, Cornelius P. Rhoades (1898–1959), chairman of a committee of the National Research Council, reported a summary of the results of the clinical trials of nitrogen mustards in Hodgkin’s disease and other malignancies. Rhoades was the director of the Sloan-Kettering Institute for Cancer Research and the director of Memorial Hospital. The three detailed reports of the effect of nitrogen mustard in human cancer were published in the same year. Goodman and Gilman’s paper is given priority based on their synthesis of the mustard compounds, extensive preclinical studies, and careful clinical evaluation in concert with Maxwell Myer Wintrobe and William Dameshek, two of the leading academic hematologists of the day. In their classic paper, Goodman and colleagues reported treating sixty-seven patients with Hodgkin’s disease, lymphosarcoma, and acute and chronic lymphocytic and myelogenous leukemia. Most were previously treated with X-irradiation and were in the late stages of their disease. Several dramatic responses occurred, especially in Hodgkin’s disease. (2) This finding was also reported independently by Leon Jacobsen and colleagues at the University of Chicago, and John Frederick Wilkinson and Frank Fletcher at the Manchester Royal Infirmary in simultaneous studies.
As an aside, Goodman and Gilman used the detailed notes from their medical school course in pharmacology at Yale to convert and expand them into a textbook, The Pharmacological Basis of Therapeutics: A Textbook of Pharmacology, Toxicology and Therapeutics for Physicians and Medical Student first published in 1941. It became a classic. In 1958, as a third-year medical student, I recall saying that if I were stranded on a tropical island and could only have one medical text to use, I would take “Goodman and Gilman” as the only book I would want to have with me. It was full of integrated biochemistry, physiology, pharmacology, and therapeutics. I used the second edition, published in 1956. It is now in its thirteenth edition.
The clinical study directed by Goodman and coworkers was conducted at hospitals in New Haven, Salt Lake City, Boston, and Portland, presaging later multicenter collaboration for clinical trials. Nitrogen mustard became a mainstay of treatment for Hodgkin’s disease, and twenty-five years later was incorporated into a curative four-drug regimen. (3) Intravenous nitrogen mustard was difficult to use; therapists had to protect themselves from skin contact or inhalation and the patient could suffer burns from extravasation or vein damage. Other molecules, congeners, that were easier to use and had similar tissue effects were subsequently developed.
The synthesis of the first effective nitrogen mustard, mechlorethamine, led ultimately to a series of drugs that act to add an alkyl group to the guanine in DNA, preventing DNA from replicating and thus, the cell from multiplying. These anticancer agents have been collectively referred to as alkylating agents. (Table 1) These initially supplemented surgical excision when possible, and radiation therapy. The most useful application of nitrogen mustard was in multicentric cancers such as Hodgkin lymphoma, where surgery was not an option.
The oral alkylating agents busulfan and chlorambucil were synthesized and tested at the Chester Beatty Institute in London and their use described in 1953. Cyclophosphamide was synthesized in Germany and introduced in about 1960. Busulfan, cyclophosphamide, and chlorambucil are pro-drugs and can be given orally, undergoing conversion in the tissues to their active forms. The specific tissue effects of nitrogen mustard and related compounds, including DNA cross-linking and alkylation of DNA, took several decades to unravel. Procarbazine, a methylhydrazine derivative, has several mechanisms of action but can also directly damage DNA through an alkylation reaction. It was developed in the early 1960s and was soon recognized as an active agent in the treatment of lymphoid malignancies. It was approved for use in 1969 and became one of the four drugs eventually used to treat and, in combination with three other drugs, cure advanced Hodgkin’s disease.
The wartime observations of the effects of mustard compounds on proliferative tissue ushered in the era of chemotherapy for cancer. There are now many agents available of varied chemical structures, mechanisms of action, and biological effects, supplemented or sometimes replaced by various types of immunotherapy. Paul Ehrlich coined the term “chemotherapy” to denote the use of chemicals to treat disease. A review of the development of cancer chemotherapy from the early 1900s to the development of anti-cancer chemicals that have led to the increased survival and cure of patients was published in 2008, 3 as was a status report on the chemical approach to hematological malignancies. (4)
1. Adair FE, Bagg HJ Experimental and(1.) Adair FE, Bagg HJ Experimental and Clinical Studies on the treatment of cancer by dichloretyhylsulfide (mustard gas). Ann Surg 1931;93:190-99, 1931.
(2). Goodman LS, Wintrobe MM, Dameshek W, Goodman MJ, Gilman A, McClennan MT. Nitrogen mustard therapy: use of methyl-bis (beta-chlorethyl) amine hydrochloride for Hodgkin’s disease, lymphosarcoma, leukemia and certain allied and miscellaneous disorders. J Am Med Assoc 1946;132:126-32.
(3.) Devita VT Jr, Chu E. A history of cancer chemotherapy. Cancer Res 2008;68:8643-52.
(4.) Lichtman MA. Battling the Hematological Malignancies: The 200 Years; War Oncologist 2008;13;126-138
Written November 2020