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?