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this inhibition slows down the tumor growth. Intravenously administered 5-FU is
inactivated by dihydropyrimidine (DPD), an enzyme that exhibits wide variations
among individuals. Patients with low DPD accumulate excessive 5-FdUMP, which
causes severe gastrointestinal and neurological toxicities.
Approximately 3 % of Caucasians have a defi ciency of the enzyme DPD. Patients
with a DPD defi ciency who receive 5-FU have a prolonged half-life of the active
compound and may experience life-threatening and even fatal toxicities including
neurotoxicity and hematopoietic toxicity. On the other hand, overexpression of
DPD in tumor tissues is associated with 5-fl uorouracil resistance, as determined by
gene expression profi ling. This suggests the need to individualize therapy to avoid
enhanced toxicity. Cimetidine is an inhibitor of DPD and, therefore, concomitant
use of cimetidine with 5-FU can result in similar toxicities. There are numerous
mutations that may occur, making the assay diffi cult to perform and standardize.
UGT1A1 Test as Guide to Irinotecan Therapy
Although most patients tolerate the chemotherapeutic agent irinotecan (Campostar ® )
for colorectal cancer quite well, some patients are genetically predisposed to severe
side effects. Earlier studies with the irinotecan demonstrated that the highly variable
toxicity was related to variability in the drug’s metabolism. It was subsequently
found that patients with two copies of one version of the UGT1A1 gene had few
side effects at the standard dosage. Patients with only one copy of this version had
more diffi culty, and patients with two copies of the alternative version were at high
risk for severe side effects. Therefore, relying on one standard dose meant that some
of those patients received subtherapeutic doses of irinotecan and others received
more than they could manage. UGT1A1 test was developed as a companion diag-
nostic to irinotecan therapy.
Third Wave Technologies had received FDA approval for its UGT1A1 test kit in
2005, but initially the test was only available only to patients enrolled in studies at
the University of Chicago. Later on, the Mayo Clinic (Rochester, MN) licensed this
test from the University of Chicago. Through this licensing agreement, Mayo
Clinic’s reference laboratory, Mayo Medical Laboratories (MML), make the test
available to patients nationwide. Dosing based on the UGT1A1 test has the dual
advantage of reducing side effects and increasing benefi t of this important drug.
Because of this study, the FDA required amendment of the package insert for
Camptosar ® (Pfi zer) to include a warning that patients with a particular UGT1A1
genotype should receive a lower starting dose. The UGT1A1 test enables the physi-
cian to know in advance which patients are at risk. Those patients could be given
reduced doses of irinotecan or other chemotherapy drugs. Genotyping results of
UGT1A1 gene appear to predict severe adverse reactions more straightforward than
the pharmacokinetic parameters or the phenotypes of the enzymatic activity.
10 Personalized Therapy of Cancer