During this symposium, faculty
participated in a roundtable discussion of the relative merits and weaknesses
associated with use of the fluorinated pyrimidines. Dehydropyrimidine
dehydrogenase (DPD) deficiency and the impact of this deficiency on the efficacy
of fluorouracil-based therapies was a major focus of the discussion. Other
topics discussed included appropriate follow-up for patients receiving oral
therapy and reimbursement issues associated with oral vs intravenous therapy.

Dehydropyrimidine Dehydrogenase Deficiency

Leonard Saltz, MD: In this general discussion, we’ll talk
about the direction in which we see oral fluorinated pyrimidines going. The
issues there are going to be in terms of their development.

Let’s go back to the creation. It’s day six. Human beings
are being created. You’re putting the person together and you throw in DPD.
Why? It’s fascinating to me that people who are DPD deficient live all their
lives without knowing it unless they are exposed to fluorouracil (5-FU).
Eniluracil is a phenomenally effective inhibitor and yet unbelievably nontoxic.
So what is this enzyme doing there?

Robert Diasio, MD: We talk about DPD and fluorouracil metabolism
as being a catabolic enzyme. But in terms of metabolism itself within the body,
we can also look upon DPD as being an anabolic enzyme and a synthetic enzyme in
that it is one of the enzymes responsible, eventually, for the synthesis of beta
alanine. Beta alanine has been suggested, by some people, at least, to be
potentially important as a neurogrowth factor, although the evidence is very
weak.

But there’s another symptom of DPD deficiency that’s been
described in children that results in growth and mental retardation. A number of
cases have been described, mainly in the Benelux countries (Belgium, The
Netherlands, and Luxembourg), where they happen to do amino acid analyses on all
newborns. They were the first to describe DPD deficiency. They discovered an
elevated peak and couldn’t explain what it was; it turned out to be uracil.
They found this to be associated with microcephaly, growth retardation,
developmental defects, and seizures in some of these children. So beta alanine
may have a role in terms of development. That’s why I would ask why DPD is
needed. It wasn’t put there just to cannibalize 5-FU.

Peter O’Dwyer, MD: What about other altered pyrimidines like
methyl uridine that are important metabolically, for which you still wouldn’t
want very high levels?

Dr. Diasio: It’s not clear. There’s very little information
about the role of these other pyrimidine compounds.

Jean Grem, MD: It’s even more complicated because there have
been cases described where there are two siblings who are both genotypically DPD
deficient and yet one of them has all these neurologic deficits and the other
one is perfectly normal. So it’s more complicated than simply asking why you
have DPD deficiency. For people who are absolutely deficient, it’s possible
that something else may be missing.

Dr. Diasio: At the molecular level, some of those mutations have
now been shown to be the same. Skipping of axon 14 actually has been shown to be
responsible. We’ve shown it in some of the 5-FU patients.

Leonard Saltz, MD: So patients who find out that they are DPD
deficient when they have a bad experience with 5-FU, presumably have a lesser
degree of dysfunction—but some function—because they don’t have
developmental abnormalities. Phenotypically, is there anything to alert
somebody?

Dr. Diasio: No. It’s a true pharmacogenetic syndrome.

Dr. Saltz: If it’s really pharmacogenetic, then it’s harder
to justify the existence of the enzyme in the first place. It may be something
you need early on and then it’s superfluous.

Dr. Diasio: Yes. It may be very important in fetal development.

Dr. Saltz: Except if that were true, we’d have to postulate
that the people who clinically had deficiencies have lost them somewhere along
the way; that they had to have had it to develop normally.

Dr. Diasio: Or they had an exogenous supply of beta alanine or
some of these other factors.

Dr. Grem: For these children there may be some in utero deficit
or dietary deprivation. All that isn’t really known. DPD protein is a huge
molecule and very complex, 33 iron atoms. Its substrates are these tiny
pyrimidine bases and it doesn’t seem logical that you would have this huge
enzyme to handle these little bases.

John Marshall, MD: Is it inducible? Can you change its
expression?

Dr. Diasio: Not really. Not in the same way as a number of other
enzymes that we traditionally think of as being inducible.

Dr. Saltz: We don’t understand the regulation of its
expression.

Peter Danenberg, MD: It’s likely that this enzyme also might
have some undiscovered role.

Dr. Diasio: We’ve looked at the homology to see if there’s
anything else. We wondered if it was related to other enzymes. It doesn’t seem
to share homology with a lot of these other enzymes. Going to the gene bank, we
haven’t been able to find a similarity.