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From Weapon to Wonder Drug

From: The Hospitalist, February 2007

How deadly mustard gas became the first effective chemotherapeutic agent

by Johnathan Frunzi

FLASHBACK

Gas! Gas! Quick, boys! An ecstasy of fumbling, Fitting the clumsy helmets just in time; But someone still was yelling out and stumbling And flound’ring like a man in fire or lime.
—Wilfred Owen, Dulce et Decorum Est (1917)

In virtually every hospital around the world, oncology patients are treated with constantly evolving life- and limb-saving protocols. Cancer has plagued mankind for thousands of years. Records of cancer exist from as early as the ancient Egyptian era. The famous Edwin Smith Surgical Papyrus, dating to 1,600 B.C., describes a man with “bulging tumors on his breast.” The translation of the treatment for this case simply reads: “There is no treatment.” Unfortunately, the history of chemotherapy lags behind that of the disease it treats by at least 4,000 years. And ironically, the first modern day anticancer drug was spawned from a deadly World War I weapon.

Sulfur mustard, or mustard gas, has the dubious distinction of being one of the original chemical weapons. Bis-(2-chloroethyl) sulfide was first synthesized by London Institute of Physics Co-founder Frederick Guthrie in 1860. Guthrie, a profound believer in the advancement of science through experimentation rather than discussion, first documented the toxic effects of mustard gas by applying his mixture of ethylene and sulfur dichloride to his own skin, thus joining other notables in the halls of self-experimentation.

Mustard gas was mass-produced under the name LOST (an acronym fashioned from the names of its developers) for the German company Bayer AG during the first decade of the 20th century. Unfortunately, this proved to be perfect timing for the introduction of chemical warfare by the German army in 1917. The first strike was against Canadian troops. One year later the British used the same agent to destroy the “impregnable” Hindenburg Line. This culmination of the storied allied forces’ 100 Days Offensive ultimately led to the end of the First World War.

Various permutations of this compound were used sporadically by numerous world powers over the next 25 years. The malevolent use of mustard gas may be responsible for nearly 100,000 deaths and approximately five times as many wartime injuries. In fact, sulfur mustard gas—not a gas or a mustard, but rather a yellowish-brown vaporized liquid with a mustard seed-like odor—is known primarily as an incapacitant rather than as a lethal weapon. The effects of this poison may remain hidden for two to 24 hours after exposure.

Sulfur mustard is a vesicant. It exerts its effects on the body’s mucous membranes. The skin and the eyes are among the first organs to be affected. The toxicity of this agent is dose-dependent. While lower concentrations can cause symptoms as minor as skin irritation and conjunctivitis, higher titers can lead to morbid consequences such as necrotic ulcerations of the skin and blindness. At still higher concentrations, inhaled vapors can damage the mucous membrane lining of the respiratory tract, leading to hemorrhagic pulmonary edema.

Sulfur mustard also causes chronic sequelae. After exposure, surviving victims might exhibit nausea, vomiting, alopecia, and increased vulnerability to infection. These later symptoms are the result of the poison’s ability to act as an alkylating agent, cross-linking DNA and preventing the normal sequence of DNA replication. The organs primarily affected are the lining of the gastrointestinal tract and the bone marrow, due to their inherent high mitotic activity.

Despite its sinister history, mustard gas has played a key role in the development of anti-cancer chemotherapeutic agents and may justly be referred to as the egg from which medical oncology has hatched. The history of medicine contains many tales of accidental discovery, but how did a deadly gas become the first effective chemotherapeutic agent?

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.

Frederick Guthrie
Frederick Guthrie

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

  1. Pratt WB, Ruddon RW, Ensminger WD, et al. The Anticancer Drugs. 2nd ed. New York: Oxford University Press; 1994.
  2. Faguet GB. The War on Cancer: An Anatomy of Failure, a Blueprint for the Future. Dordrecht, Netherlands: Springer Press; 2005.
  3. Baguley BC, Kerr DJ, eds. Anticancer Drug Development. New York: Academic Press; 2002.
  4. 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.
  5. Kazin RA, Lowitt NR, Lowitt MH. Update in dermatology. Ann Intern Med. 2001;135:124-132.

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