Wednesday, December 20, 2006

UKALL 2003 - Cyclophosphamide and Chemical Warfare

This is the one we really don't look forward to as it takes 4.5 hours at the hospital to administer. If the transport at either end is late, then we're talking a very very long day. Well, in fact it only takes about half an hour as an IV drip but they have to give you half an hour of saline beforehand and 3.5 hours afterwards to counteract one of its potential side-effects – more of that anon.

Cyclophosphamide is what is called a pro-drug – that is it doesn't act directly itself but gets changed into something else and this something else does the work.

In the case of Cyclophosphamide it is changed into aldophosphamide in the liver. Most of this is then oxidised by the enzyme aldehyde dehydrogenase (ALDH) into the pretty useless carboxyphosphamide. However, a small amount is converted into the good phosphamaride mustard and
the harmful acrolein.

Now phosphamaride mustard is pretty cool stuff! It's one of a group of substances called nitrogen mustards and the first nitrogen mustard, mustine, is on Schedule 1 of the Chemical Weapons Convention!

At the end of the first world war mustard gas was quite widely used by both sides. Although there were only isolated incidents of its use in the second world war, both sides had large stockpiles. In 1943 a U.S. stockpile in Italy was bombed exposing thousands of people. It was noticed that one of its effects was to lower the white blood count – and this led to research into its use as an anti-cancer agent.

My dad was a Gas Identification Officer in the second world war. He worked in a factory producing paint for military aircraft – a protected occupation meaning he didn't get conscripted. After air raids he would have to go out and check that the bombs dropped were not gas bombs. He also went the rounds giving talks to air raid protection people – I remember when I was a child him showing us his sample kit which he would get people to sniff so they would be able to recognise chemical warfare agents. Blimey – if he was found with that stuff today they'd arrest him as a terrorist!

A couple of chemistry diagrams to demonstrate the relationship betwe
en cyclophosphamide and mustard gas.

At the top is a cyclophosphamide molecule, below mustard gas. Those two chlorine arms on each side of the nitrogen and sulphur atoms are what make them similar.

And lastly in this little digression – its called mustard because its smell is vaguely similar to edible mustard, not because edible mustard is otherwise faintly related.

The Acrolein is the reason behind all the hydration before and after. It is toxic to the surface of the bladder and can cause hemorraghic cystitis!

Phosphamaride mustard doesn't have much effect in the bone marrow (or liver) as the cells here have high levels of ALDH. Where it does have effect is on leukaemic blood cells where, and they're not quite sure how, it gets to work on the DNA causing cell death.

Usual range of side-effects: nausea, hair-loss, low WBC etc etc as well as the bladder problems mentioned above.

Today, neutrophils and platelets permitting, is Kezia's cyclophosphamide day.

P.S. I have added some dosing information to the post concerning Methotrexate.

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