Tuesday, February 6, 2007

UKALL 2003 - 6-Mercaptopurine

Also more commonly known simply as 6-MP, this is given orally at various stages of the first year of treatment and then daily throughout the maintenance phases.

Again I am indebted to Patty Feist (link on right) for her explanation of its mode of action. It appears to have three modes of action. In the liver 6-MP is converted to a corresponding ribonucleotide (i.e. links to a ribose sugar – see the post on cytarabine). This inhibits the conversion of a compound called inosinic acid to adenylic acid which is needed to make the DNA base adenine.

In its second mode of action it also inhibits the conversion of inosinic acid to xanthylic acid that is necessary for the synthesis of guanylic acid necessary for the synthesis of the DNA base guanine.

Finally, it also works by being incorporated into nucleic acids as thioguanosine deoxyribose, rendering the resulting nucleic acids (DNA, RNA) unable to direct proper protein synthesis. Thus in this case we're changing the base rather than the sugar as is the case with cytarabine. (See this abstract)

Some people have different levels of TPMT (thiopurine methyltranserase - the enzyme that metabolizes 6-MP) activity that controls the first two modes of action (but not the third). This is controlled genetically (good explanation of this here). In fact, 1 in 300 individuals cannot break down 6-MP at all. In the UKALL 2003 protocol this is tested at diagnosis and later on, if found necessary due to adverse reactions.

In an earlier clinical trial UKALL 1997 the related drug 6-Thioguanine (6-TG) was found to increase remission death rates in comparison with 6-MP and so is no longer used. However, it would seem to be still used in other protocols (e.g the CCG 1961 protocol that Patty Feist's son was on).

It will be taken at night (see this paper on chronotherapy), at least one hour after a meal and with no recent intake of milk (see this abstract) as a compound in milk converts the 6-MP into useless by-products

See this link on Gertrude Elion, the discoverer of 6-MP and 6-TG.

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