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Vol. 29, Issue 4, 601-605, April 2001
Department of Pharmacology, Mayo Medical School/Mayo Graduate
School/Mayo Clinic, Rochester, Minnesota
Thiopurine drugs are used to treat patients with neoplasia and
autoimmune disease as well as transplant recipients. These agents are metabolized, in part, by S-methylation catalyzed
by thiopurine methyltransferase (TPMT). The discovery nearly two decades ago that levels of TPMT activity in human tissues are controlled by a common genetic polymorphism led to one of the best
examples of the potential importance of pharmacogenetics for clinical
medicine. Specifically, it is now known that patients with inherited
very low levels of TPMT activity are at greatly increased risk for
thiopurine-induced toxicity such as myelosuppression when treated with
standard doses of these drugs, while subjects with very high activity
may be undertreated. Furthermore, recent reports indicate that TPMT may
be the target for clinically significant drug interactions and that
this common genetic polymorphism might be a risk factor for the
occurrence of therapy-dependent secondary leukemia. In parallel with
these clinical reports, the molecular basis for the TPMT polymorphism
has been determined as a result of cloning and characterization of the
human TPMT cDNA and gene. Those advances led to the description and
characterization of a series of single nucleotide polymorphisms that
result in low levels of enzyme activity as well as a polymorphic
variable number tandem repeat within the 5'-flanking region of the TPMT
gene that may "modulate" level of enzyme activity. As a result of
these observations, the TPMT genetic polymorphism represents a model system for the way in which basic pharmacogenetic information is
developed and applied to clinical medicine.
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