Have you heard of mustard gas? It’s a chemical warfare agent. It is also the parent compound of an old chemotherapy agent called cyclophosphamide (SIGH-CLO-FOS-FUH-MIDE) that we use for many types of childhood cancer. Of note, its called mustard gas because when its used in its impure form it is yellow and has an odor of a mustard plant, but it isn’t derived from the plant. When I say that cyclophosphamide is old, I mean it’s pretty old. It was the 8th drug that the FDA approved for anticancer therapy in 1959.
After noticing that military personnel exposed to mustard gas had problems with their bone marrow, it was investigated as a chemotherapy agent. A team of scientists took mustard gas and made an “inactive transport form”. This means the drug is inactive and then by some process it becomes biologically active or toxic in the body. The official term for this type of drug is called a pro-drug.
Cyclophosphamide falls into a group of chemotherapy drugs called alkylating agents. These drugs add an alkyl group to the DNA (for my organic chemistry fans – it adds it to the guanine base of DNA, at the number 7 nitrogen atom of the purine ring). Anyway, cells that divide rapidly, will have more of these alkyl groups added compared to normal cells and thus the resultant DNA is not normal and the cell will die. Because cancer cells divide more rapidly than normal cells, they are affected more.
After cyclophosphamide enters the body, it is metabolized by the liver into two main metabolites or products. The first metabolite is called phosphoramide mustard and this metabolite is actually what adds that alkyl group to DNA. The other metabolite is called acrolein which passes into the urine and if it sits in the bladder too long it can become corrosive and cause the bladder to bleed. This is called hemorrhagic cystitis when it happens. A bleeding bladder is very painful and can cause major problems. Luckily there is a drug called mesna which is given with cyclophosphamide which binds and neutralizes acrolein. This, in addition with giving a lot of IV fluids so that urine doesn’t stay in the bladder for long is so effective that I haven’t personally seen hemorrhagic cystitis from cyclophosphamide.
These old drugs are highly effective, but they are also highly toxic and they are a far cry from the more precise drugs that are currently in development for many adult cancers. While I suspect that these “old” drugs will continue to be utilized for a long time, my hope is that by the time I retire we can use less of them and add in more precise, less toxic medicines to our regimens.
#ChildhoodCancer365 #morethanfour
