267Thiopurine Methyltransferase
Polymorphisms in the thiopurine methyltransferase (TPMT) gene have been
convincingly associated with the therapeutic effi cacy and toxicity of thiopurine che-
motherapeutic agents: 6-mercaptopurine and 6-thioguanine. TMPT-defi cient
patients are at high risk of developing severe hematopoietic toxicity if treated with
conventional doses of thiopurines. Insights gained from studies of the TPMT poly-
morphism illustrate the potential of pharmacogenomics to optimize cancer therapy
by avoiding toxic side effects in genetically distinct subgroups of patients.
Genetic polymorphism at this gene locus is associated with diffi culty in achiev-
ing an effective dose of chemotherapeutic drugs in children with leukemia. Children
with inherited TPMT defi ciency exhibit severe hematopoietic toxicity when exposed
to drugs such as 6-mercaptopurine, whereas those with a high activity form of the
enzyme require high doses of the drug to achieve any clinical benefi t. The TPMT
polymorphism is relatively rare, with only about 1 % of the white population being
homozygous for it, but, since these individuals show exaggerated toxic responses to
normal doses of thiopurine, TPMT phenotype may be an important factor in the
successful treatment of childhood leukemia. About 10 % of children with leukemia
are intolerant to 6-mercaptopurine because of genetic defects in mercaptopurine
inactivation by TPMT. Some centers already provide a diagnostic phenotyping ser-
vice to guide the clinical use of 6-mercaptopurine.
A pharmacogenomic test, developed at St. Jude Children’s Research Hospital,
enables physicians to predetermine patients’ TPMT activity levels based on whether
or not they have inherited the alleles associated with TPMT defi ciency. The test
classifi es patients according to normal, intermediate, and defi cient levels of TPMT
activity. Concordance between genotype and phenotype approaches 100 %. Patients
classifi ed as normal in activity − about 90 % of whites and blacks − are treated with
conventional doses. Lower doses are tailored to avoid toxicity in defi cient and inter-
mediate patients, who represent about 10 % of each of these populations. The
TPMT genetic test is well recognized in the effective clinical management of
patients with acute lymphoblastic leukemia. Adjusting the dose of 6-mercaptopu-
rine by a 10- to 15-fold decrease compared with conventional doses makes thiopu-
rine as tolerable and effective in TPMT-defi cient patients as it is in patients with
normal activity levels.
Dihydropyrimidine Dehydrogenase
Dihydropyrimidine dehydrogenase (DPD) is responsible for 80 % of the degrada-
tion of 5-fl uorouracil (5-FU), a commonly used anticancer therapy. 5-FU is a pro-
drug that requires activation to 5-fl uoro-2-deoxyuridine monophosphate (5-FdUMP)
to exert antitumor activity. 5-FdUMP inhibits tumor cell replication via inhibition of
thymidine synthase, an enzyme that is required for the synthesis of pyrimidine and
Pharmacogenetics of Cancer Chemotherapy