THE ORIGIN OF
CHEMOTHERAPY

Chemotherapy is a relatively recent development with its historical origins in observations of the toxic effects on humans exposed to chemical warfare agents, mainly mustard gas, during WWI and WWII, and to experimental studies of these agents used systemically in animals and humans preceding and during WWII.

Mustard gas is the common name for 1,1-thiobis(2-chloroethane), a vesicant chemical warfare agent synthesized by Frederick Guthrie in 1860 and first used near Ypres (Belgium) during WWI. Thus, its alternate name, Yperite.

frederick_guthrieBecause it could penetrate masks and other protective materials available during WWI, and given its widespread use by both sides of the conflict, its effects were particularly horrific and deadly. Out of 1,205,655 individuals exposed to Mustard gas during WWI, 91,198 died [1].

wwi-chemical-agentIt was at this time that mustard gas victims were first noted to develop low white blood cell counts and bone marrow aplasia. In a landmark study [2], a group of researchers at the University of Pennsylvania conducted autopsies on 75 soldiers who died of exposure to mustard gas during WWI, and reported decreased white blood cell counts and depletion of the bone marrow and lymphoid tissues. Shortly thereafter, military researchers from the US Chemical Warfare Service reported the same effects in rabbits injected intravenously with dichloroethylsulfide contaminated with mustard gas [3]. Fifteen years later the anti-cancer activity of mustard gas in experimental animal models was reported for the first time [4].

During WWII, the US’s Office of Scientific Research and Development (OSRD) funded Yale University to conduct, in secrecy, chemical welfare research [5]. These studies lead to the confirmation of the anti-tumor activity of mustard gas in murine lymphoma, and to the first human trials of nitrogen mustard reported at a Chicago meeting in early 1943 [6]. However, what brought the medical community’s attention to the Yale’s group studies and launched the era of cancer chemotherapy was a WWII incident when humans were accidentally exposed to mustard gas released during the bombardment of the Italian town of Bari by the German Luftwaffe, on December 2, 1943.


top-secret-bari-2nd-december-1943


Bari was a usually sleepy town of approximately 65,000 people located on the Adriatic shore of the Italian “boot”. Old Bari, perched on a promontory around its medieval fortified Castello Normanno Svevo and the Basilica San Nicolo, and new Bari, were transformed in late 1943 by the arrival of approximately 30 allied ships in its small harbor. Under British jurisdiction, Bari was the main supply center for British General Montgomery’s Army, and had just been designated headquarters of the American Fifteenth Air Force division.

bari-03-jpgOn the afternoon of December 2, 1943, 1st Lt. Werner Hahn piloted his Messerschmitt Me-210 reconnaissance plane over the port of Bari, in southeastern Italy. Cruising at 23,000 feet, his aircraft made a telltale contrail as he streaked across the sky, but Allied anti-aircraft crews took little notice. Still unmolested, the German pilot made a second pass over the city before turning north toward home. If Hahn’s report was promising, the Luftwaffe would launch a major airstrike against the port. Hahn reported to his superiors the suitability of Bari as a target for an air strike.

messerschmitt-me210As 1943 drew to a close, Bari’s medieval torpor and somnolent grace were shaken off by the influx of Allied shipping into its harbor. Tons of supplies were offloaded almost around the clock, transforming the once quiet town into a hive of activity. On December 2, at least 30 Allied ships were crowded into the harbor, packed so tightly they almost touched.

The port was under the jurisdiction of the British, in part because Bari was the main supply base for General Bernard Law Montgomery’s Eighth Army. But the city was also the newly designated headquarters of the American Fifteenth Air Force, which had been activated in November of that year. The Fifteenth’s primary mission was to bomb targets in the Balkans, Italy and especially Germany. Fifteenth Air Force commander Maj. Gen. James H. ‘Jimmy’ Doolittle had arrived in Bari on December 1.

The Americans had championed daylight precision bombing, but the Eighth Air Force in England was suffering terrible casualties in order to prove the theory valid. Luftwaffe strength was increasing, not decreasing, over Germany. The Fifteenth Air Force was intended to take some of the pressure off the beleaguered Eighth.

In addition to the usual war materiel, ships moored at Bari carried aviation fuel for Doolittle’s bombers and other much-needed supplies. Selection of Bari as the Fifteenth Air Force headquarters–about 75 miles from the Fifteenth’s primary airfields at Foggia–meant a large infusion of staff personnel. About 200 officers, 52 civilian technicians and several hundred enlisted men were being brought into the city.

Totally absorbed by the task of getting the Fifteenth Air Force off the ground, the Allies gave little thought to the possibility of a German air raid on Bari. The Luftwaffe in Italy was relatively weak and stretched so thin it could hardly mount a major effort. Or so Allied leaders believed.

German reconnaissance flights over Bari were seen as a nuisance. At first, British anti-aircraft batteries fired a half-hearted round or two, but eventually they ignored the German flights altogether. Why waste ammunition?

Responding to rumblings about lax security measures, British Air Vice Marshal Sir Arthur Coningham held a press conference on the afternoon of December 2 and assured reporters that the Luftwaffe was defeated in Italy. He was confident the Germans would never attack Bari. “I would regard it as a personal affront and insult,” the air marshal haughtily declared, “if the Luftwaffe would attempt any significant action in this area.” he would also “consider it a personal insult if the enemy should send so much as one plane over the city”.

sir-arthur-conningham

Not everyone was so sure that the German air force was a broken reed. British army Captain A.B. Jenks, who was responsible for the port’s defense, knew that preparations for an attack were woefully inadequate. But his voice, as well as those of one or two others, was drowned out by a chorus of complacent officers. When darkness came, Bari’s docks were brilliantly lit so unloading of cargo could continue. Little thought was given to the need for a blackout.

In the harbor, cargo ships and tankers waited their turn to be unloaded. Captain Otto Heitmann, skipper of the Liberty ship SS John Bascom, went ashore to see if the process could be speeded up. He was disappointed in his quest, but he might have been even more concerned had he known what was aboard SS John Harvey.

ss-john-herveyJohn Harvey, commanded by Captain Elwin F. Knowles, was a typical Liberty ship, scarcely different from the others moored in the harbor. Much of her cargo was also conventional: munitions, food and equipment. But the ship had a deadly secret cargo. Approximately 100 tons of mustard gas bombs were on board. The bombs were meant as a precaution, to be used only if the Germans resorted to chemical warfare.

In 1943 there was a possibility that the Germans just might use poison gas. By that point in the war, the strategic initiative had passed to the Allies, and Germany was on the defensive on all fronts. Adolf Hitler’s forces had sustained a major defeat at Stalingrad, and they had lost North Africa as well. The Allies were now on the Continent, slowly inching their way up the Italian peninsula.

Hitler, it was said, was not a great advocate of chemical warfare, perhaps because the Führer himself had been gassed during World War I. He was, however, ruthless and might be persuaded to use gas if he believed it would redress the strategic balance in his favor. Intelligence reports suggested that the Germans were stocking chemical weapons, including a new chemical agent called Tabun.

American President Franklin D. Roosevelt issued a policy statement condemning the use of gas by any civilized nation, but he pledged that the United States would reply in kind if the enemy dared to use such weapons first. John Harvey was selected to convey a shipment of poison gas to Italy to be held in reserve should such a situation occur.

When the mustard gas bombs were loaded aboard John Harvey, they looked deceptively conventional. Each bomb was 4 feet long, 8 inches in diameter and contained from 60 to 70 pounds of the chemical. Mustard is a blister gas that irritates the respiratory system and produces burns and raw ulcers on the skin. Victims exposed to the gas often suffer an agonizing death.

The poison gas shipment was shrouded in official secrecy. Even Knowles was not formally informed about the lethal cargo. Perceptive members of the crew, however, must have guessed the voyage was out of the ordinary. For one thing, 1st Lt. Howard D. Beckstrom of the 701st Chemical Maintenance Company was on board, along with a detachment of six men. All were expert in handling toxic materials and were obviously there for a purpose.

John Harvey crossed the Atlantic without incident, successfully running the gantlet of German submarines that still infested the ocean. After a stop at Oran, Algeria, the ship sailed to Augusta, Sicily, before proceeding to Bari. Lieutenant Thomas H. Richardson, the ship’s cargo security officer, was one of the few people on board who officially knew about the mustard gas. His manifest clearly listed 2,000 M47A1 mustard gas bombs in the hold.

m47Richardson naturally wanted to unload the deadly cargo as soon as possible, but when the ship reached Bari on November 26, his hopes were dashed. The harbor was crammed with shipping, and another convoy was due shortly. Dozens of vessels were stacked up along the piers and jetties, each waiting its turn to be unloaded. Since the lethal gas was not officially on board, John Harvey was not about to be given special priority.

For the next five nerve-racking days, John Harvey rode peacefully at anchor at Pier 29 while Captain Knowles tried vainly to get British port officials to speed things up. This was difficult, because he was gagged by the secrecy that surrounded the gas shipment. How could he get officials to act when he was not even supposed to know that he was carrying the mustard gas in the first place?

While Knowles fretted, German reconnaissance pilot Hahn had returned to base. His positive report about conditions at Bari set in motion a raid that had been discussed and planned some time before. The Bari attack was the product of a planning session between Luftwaffe Field Marshal Albert Kesselring and his subordinates. The Allied airfields at Foggia were discussed as possible targets, but Luftwaffe resources were stretched too thin to permit the effective bombing of such a large complex of targets.

It was Field Marshal Wolfram von Richthofen, commander of Luftflotte 2, who suggested Bari as an alternative. A cousin of famed World War I ace Manfred von Richthofen, the field marshal was an experienced officer who had served in Poland and the Soviet Union as well as in the Battle of Britain. His advice, Kesselring knew, was sound. Richthofen believed that if the port was crippled, the British Eighth Army’s advance might be slowed and the nascent Fifteenth Air Force’s bomber offensive delayed. Richthofen told Kesselring that the only planes available for such a task were his Junkers Ju-88 A-4 bombers. With luck, he might scrape together 150 such planes for the raid.

When the strike force was mustered, there were only 105 Ju-88s available for the mission. But the element of surprise, coupled with an attack at dusk, might shift the odds in the Germans’ favor. Most of the planes would come from Italy, but Richthofen purposely wanted to obfuscate matters by using a few Ju-88s from Yugoslavia. If the Allies thought the entire mission originated from there, they just might misdirect retaliatory strikes to the Balkans.

flightgermanju88sThe Ju-88 pilots were ordered to fly their twin-engine bombers east to the Adriatic, then swing south and west. British anti-aircraft would probably expect an attack–if any–to come from the north, not from the west. The Ju-88s were also supplied with Duppel, thin strips of tinfoil cut to various lengths. The tinfoil registered like aircraft on radar screens, producing scores of phantom targets.

The aim of the German pilots was to arrive over Bari around 7:30 p.m. Parachute flares would be released first to light the way for the attacking aircraft, and the Ju-88s would come in low, trying to get under Allied radar that was already confused by the Duppel.

The Germans arrived at Bari on schedule. First Lieutenant Gustav Teuber, leading the first wave, could hardly believe his eyes. The docks were brilliantly lit; cranes stood out in sharp relief as they unloaded cargo from the ships’ gaping holds, and the east jetty was packed with ships.

Scores of Ju-88s descended on Bari like gigantic birds of prey, their attack illuminated by the city’s lights and German flares. The first bombs hit the city proper, great geysers of smoke and flame marking each detonation, but soon it was the harbor’s turn. Some 30 vessels were riding at anchor that night, and each ship’s crew had to respond to the emergency as best they could. Surprise was total, and some ships had to function without a full complement, since many sailors were on shore leave.

The German flares gave sailors the first inkling of the impending attack. Aboard John Bascom, the second officer, William Rudolf, saw the flashes and alerted Captain Heitmann. John Bascom‘s gun crew sprang into action, joining the barrage that shore batteries were now hurling into the sky. Tracer bullets laced the air, but the anti-aircraft fire was largely ineffective.

There was no time to cut anchor cables and get underway; crews along the east jetty watched helplessly while a creeping barrage of German bombs came ever closer to their vulnerable vessels. Joseph Wheeler took a direct hit and exploded into flames; John Motley took a bomb in its No. 5 hold. John Bascom, anchored next to John Motley, was next in line for punishment.

highflight-disaster-at-bari4John Bascom shuddered under a rain of bombs that hit her from stem to stern. One of the explosions lifted Captain Heitmann off his feet and slammed him against the wheelhouse door. Momentarily stunned, his hands and face bloody, Heitmann saw the body of Nicholas Elgin sprawled nearby, blood pumping from a head wound, his clothes torn off by the force of the blast.

The ship’s bridge was partly destroyed, the decks were buckled and debris was everywhere. There was nothing left to do but abandon ship. Ignoring his own wounds, Heitmann ordered the crew into the single undamaged lifeboat. By now, the entire harbor was a hell on earth, where yellow-orange flames leaped into the air, producing dense columns of acrid smoke. Ships were in various stages of burning or sinking. When flames reached munitions-laden holds, some exploded. The surface of the water was covered by a viscous scum of oil and fuel, blinding and choking those unlucky enough to be in the water.

Meanwhile, the crew of John Harvey was engaged in a heroic battle to save their ship. The vessel still was intact and had sustained no direct bomb damage. Nevertheless, she had caught fire, and the situation was doubly dangerous with the mustard gas bombs aboard. Captain Knowles, Lieutenant Beckstrom and others on board refused to leave their posts, but their heroism was ultimately in vain.

Without warning, John Harvey blew up, disappearing in a huge, mushroom-shaped fireball that hurled pieces of the ship and her cargo hundreds of feet into the air. Everyone on board was killed instantly, and all over the harbor the force of the concussion knocked men off their feet. The blast sent out multihued fingers of smoke like a Fourth of July fireworks celebration and made the harbor as bright as day.

robert-rowan_archeoclub-gela-it_01The men aboard USS Pumper, a tanker carrying aviation fuel, were witnesses to John Harvey‘s last moments. Air initially rushed into the vortex of the blast, then the concussion radiated out to knock the tanker 35 degrees to port. Pieces of the chemical bombs were thrown hundreds of feet in all directions, and tons of mustard oil were vaporized.

Meanwhile, Heitmann and his surviving crew managed to reach the tip of the east jetty, around a lighthouse that was located at its north end. He had about 50 men. Many were badly wounded, and some were so badly burned that the slightest touch brought agony. At first the lighthouse area seemed a refuge, but it soon became apparent it was more of a deathtrap. A sea of flames cut Heitmann and his men off from following the jetty’s long spine into the city, where they might have been relatively safe.

While the sailors waited to be rescued, Ensign K.K. Vesole, commander of John Bascom‘s armed guard detachment, was having difficulty breathing. Many of the other men were gasping, but it was Vesole who noted something strange about the smoke. ‘I smell garlic,’ he said, without realizing the implications of his remark. A garlic odor was a telltale sign of mustard gas. The gas had become liberally intermixed with the oil that floated in the harbor and lurked in the smoke that permeated the area.

Mustard gas-laced oil now coated the bodies of Allied seamen as they struggled in the water, and many swallowed the noxious mixture. Even those not in the water inhaled liberal doses of gas, as did hundreds, perhaps thousands, of Italian civilians. A launch dispatched from Pumper rescued Captain Heitmann and the other John Bascom survivors from the east jetty, but their troubles were just beginning.

The German raid began at 7:30 p.m. and ended 20 minutes later. German losses were very light, and they had succeeded beyond their most sanguine expectations. Seventeen Allied ships were sunk and another eight were damaged, causing Bari to be dubbed the ’second Pearl Harbor.’ The Americans sustained the highest losses, losing the Liberty ships John Bascom, John L. Motley, Joseph Wheeler, Samuel J. Tilden and John Harvey. The British lost four ships, the Italians three, the Norwegians three and the Poles two.

2guerr3867The next morning survivors woke to a scene of utter devastation. Large parts of Bari had been reduced to rubble, particularly the medieval old town. Portions of the city and the harbor were still burning, and a thick pall of black smoke hung in the sky. There were more than 1,000 military and merchant marine casualties; about 800 were admitted to local hospitals. The full extent of civilian casualties may never be known. Conservative estimates hover around 1,000, though there were probably more.

bari-harbour-attackFortunately, Bari was the site of several Allied military hospitals and related support facilities. Some were housed at the Bari Polyclinic, built by Mussolini as a showcase of Fascist health care. The Polyclinic was home to the 98th British General Hospital and the 3rd New Zealand Hospital, among others. Those facilities received many of the mustard gas victims that began to appear.

Casualties from the raid began pouring in until the hospitals were filled to overflowing. Almost immediately some of the wounded began to complain of ‘gritty’ eyes, and their condition worsened in spite of conventional treatment. Their eyes were swollen, and skin lesions began to appear. Swamped with wounded of all descriptions and still not realizing they were dealing with poison gas, hospital staffers allowed victims to remain in their oil-and-gas-soaked clothes for long periods.

bari-casualtyNot only were the victims severely burned and blistered from prolonged exposure, but their respiratory systems were also badly irritated. The mustard gas casualties were wracked with coughs and had real difficulty breathing, but the hospital staff seemed helpless in the face of this unknown ailment. Men started to die, and even those who did recover faced a long and painful convalescence. Temporary blindness, the agony of burns and a terrible swelling of the genitals produced both physical and mental anguish.

As the victims began to die, the doctors started to suspect that some kind of chemical agent was involved. Some physicians pointed fingers at the Germans, speculating that they had resorted to chemical warfare after all. A message was sent to Allied headquarters in Algiers informing Deputy Surgeon General Fred Blesse that patients were dying of a ‘mysterious malady.’ To solve the mystery, Blesse dispatched Lt. Col. Stewart Francis Alexander, an expert on chemical warfare medicine, to Bari.

Alexander examined the patients and interviewed them when appropriate. It was beginning to look like mustard gas exposure, but the doctor was not sure. His suspicions were confirmed when a bomb-casing fragment was recovered from the bottom of the harbor. The fragment was identified as an American M47A1 bomb, which was designated for possible delivery of mustard gas. The Germans could be eliminated as suspects; in this case, the Allies were to blame.

Alexander still did not know where the mustard bombs had originated. The doctor tallied the number of mustard deaths in each ship, then plotted the position of the ships in the harbor. Most of the victims came from ships anchored near John Harvey. British port authorities finally admitted off the record that they knew John Harvey was carrying poison gas. Alexander drew up a report detailing his findings, which was approved by Allied Supreme Commander General Dwight D. Eisenhower. [7] This would be the only episode of exposure to a chemical warfare agent during WWII. By the end of the month, 83 of the 628 hospitalized military mustard gas victims had died.

gravesSecrecy still dogged the whole affair, however. Eventually, the British and American people were told of the devastating Bari raid, but the part played by mustard gas was kept from them. British Prime Minister Winston S. Churchill was particularly adamant that this aspect of the tragedy remain a secret. It was embarrassing enough that the raid occurred at a port under British jurisdiction. Churchill believed that publicizing the fiasco would hand the Germans a propaganda coup.

Although the gas was mentioned in official American records, Churchill insisted British medical records be purged and mustard gas deaths listed as the result of ‘burns due to enemy action.’ Churchill’s attempts at secrecy may have caused more deaths, because had the word gone out, more victims, especially Italian civilians, might have sought proper treatment. Axis Sally, the infamous propaganda broadcaster, learned the truth and taunted the Allies. ‘I see you boys are getting gassed by your own poison gas,’ she sneered.

There were 628 mustard gas casualties among Allied military and merchant marine personnel. Of these, 69 died within two weeks. Most victims, however, like Captain Heitmann of John Bascom, fully recovered. But the figures do not include the uncounted Italian civilians who must have been exposed to the deadly chemical. There was a mass exodus of civilians out of the city after the raid. Some were probably gas victims who died for want of proper treatment.

[1]. Encyclopedia of the First World War: Deaths from gas attacks, http://www.spartacus.schoolnet.co.uk/FWWgasdeaths.htm
[2]. Kumbhaar EB, Kumbhaar HD. The blood and bone marrow in Yellow Cross Gas (Mustard Gas) poisoning: Changes produced in the bone marrow of fatal cases. J Med Res 40:497-507,1919.
[3]. Pappenheimer AM, Vance M. The effects of intravenous injections of Di-Chloroethylsulfide in rabbits, with special reference to its leukotoxic action. J Exp Med 31:71-95,1920.
[4]. Berenblum I. Experimental inhibition of tumor induction by mustard gas and other compounds. J Path Bact 40:549-558,1935.
[5]. Einhorn J. Nitrogen mustard: The origin oc chemotherapy for cancer. Int J Radiation Oncologt Biol Phys 11:1375-1378,1985.
[6]. Goodman LS, Wintrobe MM, Dameshek W, et al. Use of methyl-bis- (β-chloroethyl) amine hydrochloride and tris-(β-chloroethyl) amine hydrochloride for Hodgkin’s disease, lymphosarcoma, leukemia, and certain allied and miscellaneous disorders. JAMA 132:126-132,1946.
[7]. Alexander SF. Medical report of the Bari Harbor Mustard casualties. The Military Surgeon 10:2-17,1947.

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