How Poison Gas Gave Us the First Anti-Cancer Drug

It
has been called the Emperor of all Maladies. For the entirety of
human history, Cancer has been our constant companion, afflicting
young and old, rich and poor, sinner and saint alike. And for most
of that history we have been all but helpless against it. It was
not until the 19th century that advances in surgery made it
possible to safely remove certain tumours, and not until the
discovery of x-rays and radioactivity at the turn of the 20th that
less invasive treatments became available. But the most common
cancer treatment today, chemotherapy, would not emerge until the
middle of the century, and by a strange twist of fate its discovery
was made possible not by mankind’s compassion and desire to heal,
but by its age-old preoccupation with killing.

On September 3, 1943, following a long, hard-fought campaign
that had taken Allied Forces from North Africa to the gates of
Rome, the Italian Government signed the Armistice of Cassibile,
officially switching sides in the Second World War. Italy’s former
ally, Nazi Germany, was swift to respond to this betrayal. On
December 2, 105 Junkers Ju-88 bombers took off from airfields
across Northern Italy and headed South towards the port of Bari, a
major supply hub for advancing Allied forces. The bombers achieved
complete surprise, and with air defences around the port almost
nonexistent they wrought terrible destruction, sinking 28 ships,
setting shore oiling facilities ablaze, and killing nearly 2000
military personnel and civilians.

Among the ships destroyed in the attack was the American Liberty
Ship SS John Harvey, whose hold was loaded with a secret
cargo of 2000 M47A1 mustard gas bombs. Mustard gas, developed
during the First World War, belongs to a class of chemical weapons
known as vesicants or blister agents. An oily liquid with a strong
garlic-like smell, on contact with skin mustard gas inflicts severe
chemical burns that can take weeks or months to heal, and if
splashed in the eyes can induce temporary blindness. The exploding
John Harvey covered the harbour basin in a thick layer of
mustard gas, coating hundreds of sailors struggling in the water
from head to toe. A huge cloud of mustard gas vapour was also
thrown into the air and drifted into the neighbouring town. The
next day, more than 600 sailors and soldiers arrived at military
hospitals suffering from symptoms that baffled the American medics:
chemical burns, blindness, and – strangest of all – extremely low
white blood cell counts. But as the John Harvey’s cargo
was top-secret, vital information on how to treat the victims was
withheld from the medics.

Eventually, Dr. Stewart Alexander, an expert on chemical
weapons, was dispatched to Bari. Immediately recognizing the
symptoms of mustard gas exposure, Dr. Alexander was able to advise
army doctors on the proper course of treatment. But by this point
it was already too late:  83 military personnel and an unknown
number of civilians had succumbed to the gas’s effects, while many
others were severely disfigured. But these men would not die in
vain, for  after the War tissue samples collected by Dr.
Alexander were to play a pivotal role in launching a medical
revolution.

The cytotoxic or cell-killing effects of mustard gas had been
noted since the weapon’s introduction, and doctors  soon began
to wonder whether this effect could be used against cancer cells.
Early trials in the 1920s against lymphomas were unsuccessful as
the original form of the compound, sulfur mustard, proved too toxic
to human cells. In 1935, however, chemical weapons laboratories
began producing new forms of mustard gas in which the sulfur atom
was replaced with nitrogen. Of these, one compound in particular,
known as mechlorethamine or HN2, showed particular promise as it
was the least toxic to healthy human cells. In 1943,
pharmacologists Alfred Gilman and Louis Goodman at Yale University
conducted the first clinical trial of HN2 on a patient suffering
from severe lymphoma. Early results were encouraging, with the
patient’s tumours shrinking rapidly. However, the cancer cells
eventually developed resistance to the treatment and the tumours
soon returned.

Gilman and Goodman continued experimenting throughout the war,
but it was not until 1946 when Dr. Stewart Alexander’s report on
the victims of the Bari Air Raid were declassified that a
breakthrough was finally achieved. Noting the extremely low white
cell counts measured in the Bari victims, a team from the
University of Chicago’s Medical School led by Leon O. Jacobson
turned their attention to leukaemia, a cancer of the bone marrow
that results in the overproduction of abnormal blood cells, leading
to severe anemia, reduced clotting ability, and a compromised
immune system. HN2 proved spectacularly effective, and after
several more years of research was developed into the world’s first
chemotherapy drug, sold under the brand name Mustine.