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Web Guide 1: Robert B. Diasio, MD
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Professor of Pharmacology & Medicine
Chairman, Department of Pharmacology & Toxicology
University of Alabama, Birmingham |
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chemotherapy pharmacogenetics
A number of rare genetic syndromes are now recognized as responsible
for the inappropriate metabolism of several cytotoxic agents. One
such genetic syndrome — a mutation in the promoter region of
the gene UGT-1A1 — involves the metabolism of CPT-11. This
is the same mutation encountered in hyperbilirubinemic states such
as the Crigler-Najjar syndrome and Gilbert’s disease. About
5-10% of the population has this genetic mutation, which results
in severe diarrhea in patients receiving CPT-11.
Another pharmacogenetic syndrome associated with chemotherapeutic
agents is DPD (dihydropyrimidine dehydrogenase) deficiency. For
the past 12 years, we have studied this syndrome, which is not uncommon.
Interestingly, patients who are heterozygotes for this autosomal
co-dominant inherited defect present with very severe toxicity from
5-FU, which is metabolized by DPD.
If the enzyme isn’t present, the patient essentially receives
an overdose. We believe the DPD deficiency may contribute to some
of the toxicity encountered with the Saltz regimen.
clinical detection of metabolic abnormalities
Currently, clinical observation is the principal method for detecting
these metabolic abnormalities. With CPT-11, even a slightly elevated
baseline bilirubin might raise suspicion that there could be a problem
with metabolism. DPD deficiency, on the other hand, is a classic
pharmacogenetic syndrome. We do not recognize any abnormality until
the patient is treated with the drug. In patients who have received
the Saltz regimen, DPD deficiency and abnormalities in UGT-1A1 are
currently being evaluated.
thymidine phosphorylase (tp) levels in tumors
We learned from the human genome project that there is homology
between TP’s genetic structure and certain angiogenesis factors,
such as platelet-derived growth factor. Of course, angiogenesis
is important in tumor growth, and this may provide an explanation
as to why we see higher levels of TP in tumors than in the adjacent
tissue. TP is important because it is also responsible for activating
capecitabine.
thymidine phosphorylase, capecitabine and
radiotherapy
In animal and cell culture studies, radiation can up-regulate
TP, and this seems to be a dose-related effect with the higher doses
of radiation being associated with further TP up-regulation. It
is fascinating — just one treatment with radiation seems to
have a prolonged effect on TP up-regulation — as much as 18-fold
for as long as 18 days. You might not even have to use a full course
of radiation therapy. Potentially, radiation may be used primarily
for its effect on TP.
We also have been studying glioblastoma cells, which have higher
levels of TP than adjacent tissue. Since capecitabine is a pro-drug
and a more polar compound that more effectively crosses the bloodbrain
barrier than 5-FU, we are conducting a phase I study in brain malignancies,
looking at the possibility of radiosensitization.
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