“Every drug is a poison in disguise, every poison is a drug in disguise”. Opined by the 16th century physician Parcelsius, this is a quote which rings true in modern medicine. The book The Emperor of All Maladies narrates the history of cancer, from its beginnings with the proposed black bile through to modern times. Chemotherapy is a topic extensively discussed in this book. I was struck by its origins: the first semi-successful chemotherapy was produced by exploiting the toxic effects of mustard gas!
How does mustard gas used in chemotherapy?
This chemical was used as a weapon during World War One, smelling strongly of mustard and garlic. Mustard gas causes devastating damage to the respiratory tract, skin and eyes. It is easily absorbed through the skin, so soldiers had nowhere to hide. The gas burns its victims, leaving them with painful blisters (it is a vesicant). The gas has many properties, including obliterating the mucous membranes of the body, thus affecting the eyes, nose and respiratory tract. There are many effects including temporary blindness, shortness of breath, abdominal pain, diarrhea, fever, sinus pain, vomiting to mention a few.
Those exposed to this chemical don’t immediately display these symptoms. It is the gradual accumulation and absorption into the skin that results in these conditions. Mustard gas (Bis(2-chloroethyl) sulfide) is soluble in lipids, meaning the chemical is stored in the body’s adipose tissue and can remain to wreak havoc for a long time.
How does it work?
The compound acts on DNA. It reacts with either an oxygen or a nitrogen atom in the DNA molecule, where a chlorine atom in the mustard gas is replaced by an atom in DNA. Thus, chlorine is eliminated from the molecule by nucleophilic substitution. The mustard gas causes alkylation (addition of a alkyl group i.e. CH3) of DNA, which essentially means the molecule gets attached to DNA. It is quite potent at what it does since it contains a sulfur atom which enhances the reactivity of the molecule. Through its reaction with DNA, a sulfonium ion is produced.
Since DNA is made of two strands, the molecule can either bind to one (called an intrastrand crosslink) or to both. This alkylation occurs mainly on the guanine nucleotides of DNA. As a result of this reaction, the shape of the DNA is disrupted, so cellular division can’t occur. Enzymes attempt to repair this damage, but it is lost cause so the instead they break apart the molecule. Thus, cell death (apoptosis) has occurred. These Alkylating agents work at any point in the life of a cell (the cell cycle), so are known as cell cycle-independent drugs.
Once the mechanism of mustard gas toxicity had been decoded, it was only a matter of time before it was used as a drug to combat cancer. The specific cancer which it was used to treat is called Childhood Leukaemia, or acute lymphoblastic leukaemia (ALL).
Once this chemical weapon was used on soldiers, autopsies confirmed that the bone marrow of the dead had been killed, so could no longer manufacture blood cells, since bone marrow is responsible for producing all the blood cells in your body from the haemopoetic stem cells residing in the marrow. What’s more, soldiers who survived the attack regularly became aenemic from the loss of red blood cells. The properties didn’t stay unnoticed, and it wasn’t long before scientists were testing the chemical on mice with lymphoma (cancer of the lymph nodes). By injecting it directly into the mice it avoided the vesicant properties. The lymphomas in mice receded in size which gave great hope to the physicians. After administering the chemical to children with ALL, there were optimistic results. Scientist thought that they had found the holy grail all those fighting cancer were searching for. Yet to everyone’s dismay, remission of cancer following most treatments with this nitrogen mustard was common. Despite this chemical not living up to the cancer-obliterating drug it was perceived to be, it still prolonged the lives of suffers which is a huge leap forward. Furthermore, this discovery paved the way towards further treatments for cancer, and scientists haven’t stopped searching.