Tuesday, January 30, 2007

UKALL 2003 - Cytarabine (Ara C)

Cytarabine, more commonly known as Ara C, is administered over four consecutive days in four blocks during Augmented BFM Consolidation, and two blocks each in Delayed Intensification I and II (in Regime C of UKALL 2003). It is administered through the Hickman Line and is generally done at home as four consecutive days visiting the hospital is a bit much for both patients and carers. You'll be given a choice of learning to do it yourself or have a community nurse visit. However, the latter is a bit infeasible if a dose falls on a weekend so I would really recommend learning to do it yourself. The hospital will train you and check you are proficient as well as providing written instructions to take home.

It's really best to have two people present when administering it so the second can both check the first is doing it right, and comfort the child. We have a two-person safety rule at work for any electrical or mechanical maintenance – the second person can catch any potentially dangerous slip-ups and assist if there are difficulties – the same is true here.

The process consists of cleaning the line with saline, injecting the drug, injecting Hepsal (Heparin Sodium – an anti-clotting agent to stop the line getting blocked) and finally saline again.

The story of the development of Cytarabine is fascinating – I will try and summarise here but go to Patty Feist's page for a more in-depth account A Tale from the Sea to Ara C. Thanks also to Patty for the graphics here.

The story starts in 1945 when a young scientist, Werner Bergmann, was collecting sea sponges (Cryptotethia crypta) on the coast of Florida. He boiled them up in acetone and instead of finding a steroid as expected, discovered a new substance similar to the DNA building-block, the nucleoside thymidine. Bergmann named the new compound Spongothymidine.

The two diagrams below demonstrate the very slight difference between the two molecules. The blue portion is known as the base, and the red part is a sugar. The base of each is the same, thymine, whilst the sugars differ slightly. In thymidine the sugar is known as deoxyribose and in spongothymidine it is arabinose.

Deoxyribose sugars (plus base) form the backbone of DNA, and ribose sugars (plus base) form the backbone of RNA. So arabinose is unlike either of them.

Early research in chemotherapy concentrated on changing the base but with the discovery of spongothymidine the focus moved to changing the sugar. John Evans and Seymour Cohen bound the sugar arabinose to another of the four DNA-bases, cytosine, making Cytosine arabinoside or Ara C, and tested its anti-cancer properties with positive results.

Here's how it works (another Patty page here).

In a cell Cytosine riboside (an RNA molecule) is converted to Cytosine deoxyribose (a DNA molecule) with the help of an enzyme. The enzyme needs to bind to the riboside and strip off an oxygen atom from the OH group (on the bottom right of the sugars in the diagrams below) to make the deoxyribose. However, if cytosine arabinoside is present, the enzyme binds to it through mistaken identity but as that OH group is on the top-right of the sugar instead, it cannot find it and cannot convert it to deoxyribose. Without the cytosine deoxyribose, new DNA cannot be made and the cell will die.

Other anti-cancer drugs are now being developed from marine organisms. Patty discusses Ara G and Clofarabine in the treatment of childhood leukaemia. Other anti-cancer drugs derived from marine organisms and currently under trial include Yondelis and Apledin derived from marine tunicates and Kalahide derived from a nudibranch (a sea slug).

This just goes to show how important biodiversity conservation is – new substances, of great scientific use, are still being found in plants and animals around the world. If we lose these, before discovering what they have to offer us, we have lost an incredible resource.

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