Thursday, February 8, 2007

UKALL 2003 - Asparaginase

Asparagine is an amino-acid produced by normal cells. It was the first amino-acid to be discovered back in 1806 in asparagus – hence its name. One of the twenty most common amino-acids. Because human cells produce their own it is not considered essential in your diet.

It is required for protein synthesis and thence the synthesis of RNA and DNA. Most lymphoblasts, however, cannot produce asparagine and depend on freely circulating (or exogenous) asparagine produced by healthy cells.

If we can wipe up all this freely circulating asparagine, then the lymphoblasts cannot reproduce and cell death (apoptosis) results.

L-Asparaginase breaks asparagine down into aspartic acid and ammonia. It was first discovered in guinea pig serum about 30 years ago and found to suppress the growth of lymphosarcomas in mice. But, as the UKALL 2003 points out, “Clearly it was not a viable option to source this agent from guinea pig serum ...”. However, it is widely found in nature and ideal sources were discovered in the bacteria Escherichia coli and Erwinia crysanthemi.

It has quite a fantastic chemical formula C1377H2208N382O442S17. With that number of atoms in a molecule, you're unlikely to find a diagram of it!

Early experiments found that the half life E. coli and E. crysanthemi asparaginase was about 10-12 hours which necessitated frequent injections and higher risks of side-effects. However, when attached to polyethylene glycol (pegylated), E. coli asparaginase has a half life of 5.73 days thus necessitating less frequent injections.

The study of Peg Asparaginase is one of the objectives of the UKALL 2003 trial. More specifically, the study aims

    To test whether with current dosing/scheduling/product used we achieve:-

    a) Adequate Asparaginase levels for the appropriate duration
    b) Whether these levels deplete asparagines?
    c) What is the rate of anti-asparaginase antibodies?
    d) How many of the reactions to pegaspase are inhibitory?

    To test the feasibility of routine Asparaginase monitoring.

Various measures on blood samples are performed – levels of asparaginase, levels of asparagine and levels of antibodies to the asparaginase. These will then be correlated to early leukaemic cell kill as measured by peripheral blood blast clearance, Day 8/15 and Day 29 marrow clearance plus the minimal residual disease estimates that form other objectives of the UKALL 2003 trial.

The Peg Asparaginase is administered as an intramuscular injection in this trial as it is thought that this route results in decreased hypersensitivity, although it may be administered intravenously in other protocols. The brand name is Oncaspar.

Numerous possible side-effects. Maybe I'll have to do an entire post on side-effects of all these drugs!

1 comment:

Anonymous said...

Yes, Angus, you WILL have to do a post on side-effects. All these drugs sound so complex and, in some cases, frankly scary, that as much info as possible is going to be necessary for anyone affected. People may not know what questions to ask if they are not forewarned.
I am speaking from a position of some bitterness currently - with regard to French medical specialists, who all seem to think they're God: hand down decrees, make judgments, don't answer questions touching the Sacred Knowledge. I know your experience of the specialists in Manchester has been very positive, but others may not be so lucky.