Fast forward 30 years to the Second World War. The interwar period resulted in numerous provisions—including the Geneva Protocol of 1929—to ban the use of chemical weapons. It was also a time during which many nations—both purposefully and accidentally—developed and stockpiled chemical agents. Thankfully, chemical weapons, including mustard gas, were not used extensively by either side during World War II. This was a period of intense—and justified—paranoia, however. General Dwight D. Eisenhower had made provisions for a stockpile of 100 tons of mustard gas on the S.S. John Harvey, which was stationed in Italy’s Bari Harbor. In December 1943, Nazi air strikes destroyed the John Harvey, among other ships, resulting in surprisingly few casualties despite the impressive amount of fire and destruction.
In the days and weeks following this catastrophe, however, survivors began to develop the familiar signs of mustard gas exposure. Lt. Col. Stewart Francis Alexander, an expert in chemical warfare, suspected exposure to the famous vapor. Autopsies of the victims reported profound lymphopenia as well as suppression of myeloid cell lines. This prompted the United States to lift the Office of Scientific Research and Development publication ban in 1946. At this time, numerous accounts were uncovered of mustard gas and its derivatives in experimental trials involving humans and cloned mice.
The first clinical trial, conducted by Louis Goodman and Alfred Gilman, involved the use of nitrogen mustard on a patient with advanced lymphosarcoma. After just four days of therapy, the patient’s tumor mass receded remarkably. Unfortunately, withdrawal of the medication due to profound neutropenia resulted in an abrupt return of the tumors. A second, shorter course resulted in a less profound reduction in tumor bulk, and a third try had no effect at all.
Interestingly, this temporary miracle with its subsequent failure illustrates two paradigms faced by medical oncologists today. Chemotherapeutic agents exert a toxic toll on the host, and tumor cells eventually develop resistance to circumvent the effects of these same medications. This is exactly why complicated protocols are used to treat patients with cancer.
Goodman and Gilman, authors of the famous medical pharmacology textbook The Pharmacological Basis of Therapeutics, used nitrogen mustard, a derivative of sulfur mustard, for their experiment. This compound, also known as mechlorethamine, is the first in-class alkylating agent, and is still used as a topical ointment in the treatment of cutaneous lymphomas. Other alkylating agents, such as cyclophosphamide, ifosfamide, and cisplatin, are used in cancer protocols worldwide.
We have not seen the last of mustard gas, which made its last acknowledged appearance in the Iran-Iraq war. Frequently, those things that are most destructive can be tamed for medical use.
The next time you have a patient receiving chemotherapy, think back to the roots of the cure. TH
References
- Pratt WB, Ruddon RW, Ensminger WD, et al. The Anticancer Drugs. 2nd ed. New York: Oxford University Press; 1994.
- Faguet GB. The War on Cancer: An Anatomy of Failure, a Blueprint for the Future. Dordrecht, Netherlands: Springer Press; 2005.
- Baguley BC, Kerr DJ, eds. Anticancer Drug Development. New York: Academic Press; 2002.
- Goodman LS, Wintrobe MM, Dameshek W, et al. Landmark article Sept. 21, 1946: Nitrogen mustard therapy. Use of methyl-bis(beta-chloroethyl)amine hydrochloride and tris(beta-chloroethyl)amine hydrochloride for Hodgkin’s disease, lymphosarcoma, leukemia and certain allied and miscellaneous disorders. JAMA. 1984;251:2255-2261.
- Kazin RA, Lowitt NR, Lowitt MH. Update in dermatology. Ann Intern Med. 2001;135:124-132.
Extremely clear and interesting. It answered lots of precise questions concerning the development of the chemical and its transition into a major chemo therapy resource. Thank you.