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Clinical Trials |
Academic Medical Center, University of Amsterdam, Emma Children’s Hospital and Department of Clinical Chemistry, 1100 DE Amsterdam [A. B. P. v. K., J. H., D. J. R., L. Z., H. V. L., P. V., A. H. v. G.]; University Hospital St. Radboud, Department of Pediatrics, 6500 HB Nijmegen [R. A. D. A.]; and Hospital Meppel-Hoogeveen, 7940 AM Meppel [J. G. M.], the Netherlands
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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A being the most abundant one (6
of 14 patients; 43%). Two novel missense mutations 496AG
(M166V) and 2846AT (D949V) were detected in exon 6 and exon 22,
respectively. Our results demonstrated that at least 57% (8 of 14) of
the patients with a reduced DPD activity have a molecular basis for
their deficient phenotype. |
INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Because 5FU has a relatively narrow therapeutic index, toxicity increases as the dose is increased, resulting in escalated plasma levels of the drug (2 , 3) . A correlation has been observed between the pretreatment activity of DPD in PBM cells and the systemic clearance of 5FU in cancer patients (7) . In this light, a pharmacogenetic disorder has recently been described concerning cancer patients with a complete or partial deficiency of DPD suffering from a severe or even life-threatening toxicity after the administration of 5FU. It was shown that a number of these patients were genotypically heterozygous for a mutant DPD allele (8, 9, 10, 11) . On the basis of a population analysis of the DPD activity, the frequency of heterozygotes has been estimated to be as high as 3% (7) . Such patients might be at risk of developing severe toxicity after the administration of 5FU.
Thus far, 17 variant DPD alleles have been identified in pediatric patients suffering from a complete or nearly complete deficiency or in tumor patients with a decreased DPD activity (11, 12, 13, 14) . Recently, Collie-Duguid et al. (11) suggested that the known variant DPYD alleles do not entirely explain the polymorphic DPD activity and toxic response to 5FU. A serious drawback of their study, however, is the fact that only 10 of the 23 exons of the DPD gene were sequenced and investigated for the presence of mutations. Thus, no sound evidence has yet been provided as to whether patients with a low DPD activity have a molecular basis for their reduced activity.
Despite the pivotal role DPD plays in the metabolism of 5FU, only a
limited number of studies have been reported describing either the
toxicity encountered in patients with a low DPD activity or the partial
analysis of the DPD gene for the presence of a mutated
DPD allele (11
, 15)
. To date, no studies have
been reported describing both the toxicity and the analysis at the
entire DPD gene for the presence of mutations. Thus, to
evaluate the importance of this specific type of inborn error of
pyrimidine metabolism in the etiology of 5FU toxicity, we performed an
analysis of the DPD activity, the entire DPD gene, and the
clinical presentation of patients suffering from severe toxicity after
the administration of 5FU. Our study demonstrates that in 59% of the
cases, a decreased DPD activity might be responsible for the observed
toxicity, with grade IV granulocytopenia being the most prevalent type
of toxicity in these patients. Furthermore, a high incidence of
mutations in the DPD gene was found, with the splice site
mutation IVS14+1GA being the most abundant one. Our results
demonstrate that at least 57% (8 of 14 patients) of the patients with
a reduced DPD activity have a molecular basis for their deficient
phenotype.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Isolation of Human PBM Cells and Granulocytes.
PBM cells were isolated from 15 ml of EDTA-anticoagulated blood by
centrifugation over Lymphoprep, and the cells from the interface were
collected and treated with ice-cold NH4Cl to lyse
the contaminating erythrocytes, as described previously
(16)
. The pellet of the centrifugation step over
Lymphoprep containing the granulocytes and erythrocytes was diluted
with 7 ml of supplemented PBS [9.2 mM
Na2HPO4, 1.3 mM
NaH2PO4, 140 mM
NaCl, 0.2% (w/v) BSA, 13 mM sodium citrate, and 5
mM glucose (pH 7.4)] and centrifuged at 800 x
g at room temperature for 10 min. To lyse the erythrocytes,
the pellet was resuspended in 7 ml of ice-cold ammonium chloride
solution (155 mM NH4Cl, 10
mM KHCO3, and 0.1
mM EDTA) and kept on ice for 5 min. After the
addition of 10 ml of ice-cold supplemented PBS, the solution was
centrifuged at 250 x g at 4°C for 10 min. The pellet
was collected and subjected to another lysis step as described above.
The pellet containing the granulocytes was washed once more with
supplemented PBS, and the final cell pellet was frozen in liquid
nitrogen and stored at -80°C until further analysis.
Determination of the DPD Activity.
The activity of DPD was determined in a reaction mixture containing 35
mM potassium phosphate (pH 7.4), 2.5 mM
MgCl2, 1 mM DTT, 250 µM
NADPH, and 25 µM [4-14C]thymine
(16)
. Separation of radiolabeled thymine from radiolabeled
dihydrothymine was performed isocratically [50 mM
NaH2PO4 (pH 4.5)] at a
flow rate of 2 ml/min by high-performance liquid chromatography on a
reversed-phase column (Alltima C18; 250 x 4.6 mm; 5 µm particle
size; Alltech Associates Inc., Deerfield, IL) and a guard column
(Supelguard LC-18-S; 5 µm particle size; 20 x 4.6 mm; Supelco,
Bellafonte, PA) with online detection of the radioactivity, as
described previously (16)
. Protein concentrations were
determined with a copper reduction method using bicinchoninic acid,
essentially as described by Smith et al. (17)
.
Determination of Intron-Exon Junctions.
The amplification of the genomic regions containing the intron-exon
boundaries of exon 4, 9, 12, 15, and 21 was performed with the
Genomewalk system using nested PCR with the primer sets as specified in
Table 1
.
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. Forward primers of exon 2, 9, 15, and 21 had a
5'-TGTAAAACGACGGCCAGT-3' extension at their 5'-ends, whereas
reverse primers had a 5'-CAGGAAACAGCTATGACC-3' extension at their
5'-ends. These sequences are complementary to the labeled -21M13 and
M13 reversed primers used in the dye-primer sequence reaction.
Amplification of all of the exons, except exons 1 and 14, was carried
out in 50-µl reaction mixtures containing 10 mM Tris-HCl
(pH 8.3), 50 mM KCl, 1.5 mM
MgCl2, 10 pmol of each primer, 200
µM each deoxynucleotide triphosphate, and 2 units of Taq
polymerase. Amplification of exon 1 was performed in the presence of
0.75 mM MgCl2 and 5% DMSO with a hot
start. Amplification of exon 14 was performed in the presence of 2
mM MgCl2. After initial denaturation
for 5 min at 95°C, amplification was carried out for 30–35 cycles (1
min at 95°C, 1 min at 50°C–65°C, and 1 min at 72°C). PCR
products were separated on 1% agarose gels, visualized with ethidium
bromide, and purified using a Qiaquick Gel Extraction kit or used for
direct sequencing.
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Statistics.
Differences in the time of the onset of toxicity and the duration of
toxicity between two groups were analyzed with the two sample
t test. In case of unequal variances, as indicated by
Levene’s test for equality of variances, the log-transformed data were
used, or the original data were tested with the nonparametric
Mann-Whitney test. Comparison of the toxicity between groups was
performed with the Mann-Whitney test. Comparison between the DPD
activity and the degree of toxicity was performed with a one-way ANOVA.
Comparisons of frequencies were carried out by the
2
test. The correlation between the activity
of DPD and the time of the onset of toxicity was studied by the
determination of the Pearson correlation coefficients and linear
regression. The level of significance was set a priori at
P 
0.05. Analyses were performed with the Statistical
Package for the Social Sciences (SPSS Inc., Chicago, IL).
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. On the basis of previous experiences, it has been suggested that
patients with a DPD activity <70% of that observed in the normal
population might be prone to develop severe 5FU-associated side effects
(15)
. According to this threshold level, in approximately
59% of the cases the DPD activity was <70% of the mean DPD activity
(10.0 ± 3.4 nmol/mg/h; n = 22) of healthy
volunteers and comparable with that observed in obligate heterozygotes
(5.5 ± 2.1 nmol/mg/h; n = 8).
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. No significant differences were observed with respect to age, gender,
or type of histology between patients with a low DPD activity and
patients with a normal DPD activity. A significant difference was
observed, however, in the time of the onset of toxicity between both
groups. In patients with a low DPD activity, the onset of toxicity
occurred on average twice as fast as that compared with patients with a
normal DPD activity (P < 0.05). A weak but significant
correlation was observed between the DPD activity and the time of the
onset of toxicity (Fig. 2)
. In contrast, no differences were observed with respect to the
duration of the toxicity, which was approximately 20 days.
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and 5
. No differences in hematological, gastrointestinal, flu-like symptoms,
or other types of toxicities were observed between both groups, with
the exception of grade IV neutropenia. It was observed that 55% of the
patients with a decreased DPD activity suffered from grade IV
neutropenia compared with 13% of the patients with a normal DPD
activity (P = 0.01).
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. In addition, the sequences flanking exon 4 were determined to allow
the detection of the frameshift mutation 295–298delTCAT. Sequence
analysis of the DPD gene of multiple patients revealed
sequence errors in the previously reported sequences of the intron-exon
boundaries of exon 2, 4, 5, 8, 15, 17, 19, and 21. The correct
sequences flanking the 23 exons of the DPD gene are listed
in Table 6
. As a result, different primer sets were used to amplify the
23 exons of the DPD gene (Table 2)
.
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. Furthermore, five patients had multiple mutations in the coding
region of the DPD gene. The missense mutation 85TC was
detected in four patients (29%), whereas the splice site mutation
IVS14+1GA was detected in six patients (43%). One patient was
homozygous for the 2194GA mutation, whereas three patients were
heterozygous for the 1627AG mutation. It has been suggested that
both the 2194GA mutation and the 1627AG mutation are common
polymorphisms (11
, 13)
. In addition, two novel mutations
496AG (M166V) and 2846AT (D949V) were detected in exon 6 and 22,
respectively. The D949V mutation has also been detected in a patient
with a complete DPD
deficiency.3
In three patients, no mutations could be detected in the coding
sequences of the DPD gene.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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To date, a number of patients with a partial DPD deficiency have been reported to suffer from severe toxicity after the administration of 5FU. On the basis of these experiences, a threshold limit for the DPD activity (70% of the mean DPD activity of a control population) has been proposed for patients at risk (15) . According to this threshold level, 59% of our patient group suffered from a partial DPD deficiency with a mean DPD activity comparable with that of obligate heterozygotes. Thus, the decreased capacity to degrade 5FU, reflected by a decreased activity of DPD, might be directly responsible for the observed toxicity in these patients. Recently, Milano et al. (15) reported that in their group of patients, only 36% suffered from a partial DPD deficiency. In contrast, our results demonstrate that in our group of patients, a partial DPD deficiency is the major determinant of 5FU-associated toxicity. Nevertheless, other factors, e.g., an increased expression of enzymes of the anabolic pathway, might provide a complementary mechanism for the observed increased sensitivity of patients to 5FU, especially in those patients with a normal DPD activity.
To date, conflicting results exist as to whether the activity of DPD might be influenced by gender (7 , 15) . It has been suggested that women might be particularly prone to the development of 5FU-associated toxicity because studies show that the DPD activity as well as the clearance of 5FU is, on average, 15% lower in women than in men (7 , 21) . In addition, the vast majority (79%) of the patients suffering from a partial DPD deficiency and severe adverse effects of 5FU are women (15) . In contrast, we did not observe a difference in gender between the patients with a low DPD activity and patients with a normal DPD activity. Thus, the prevalence of women with a partial DPD deficiency in the study reported by Milano et al. (15) remains enigmatic.
With respect to toxicity, no differences in hematological toxicity, gastrointestinal toxicity, flu-like symptoms, or other types of toxicities were observed between patients with a low DPD activity and patients with a normal DPD activity, with the exception of grade IV neutropenia. A significantly higher percentage (55%) of the patients with a decreased DPD activity suffered from grade IV neutropenia, compared with patients with a normal DPD activity (13%). A recent analysis of the toxicities encountered in cancer patients treated with 5FU showed that hematological toxicity, mainly neutropenia, is observed more frequently in patients treated with 5FU bolus than in patients receiving 5FU via continuous infusion (22) . Furthermore, no differences in risks of severe diarrhea, nausea, vomiting, and mucositis were observed between the two types of 5FU administration (22) . Thus, the higher incidence of grade IV granulopenia in patients with a low DPD activity might be related to the increased plasma levels of 5FU, mimicking the short peak plasma concentrations of 5FU that result from conventional i.v. bolus administration of 5FU. Although neurotoxic syndromes were frequently encountered in a group of patients with decreased DPD activity (15) , they appeared to be very rare in our patient population. Our findings, however, are in line with the fact that neurotoxicity is rarely reported as one of the adverse side effects of 5FU.
A conspicuous finding was that the onset of toxicity occurred approximately twice as fast in patients with a partial DPD deficiency compared with patients with a normal DPD activity. A close relationship has been demonstrated to exist between the steady-state 5FU plasma concentration as well as the AUC of 5FU in plasma and the risk of leukopenia and mucositis (3) . A sustained high level of 5FU attributable to a decreased capacity to degrade the drug might have accelerated the onset of the clinical symptoms in patients with a low DPD activity. Recently, Etienne et al. (23) have shown that not only the DPD activity but also other factors, such as age, high serum alkaline phosphatase, and elapsed time during infusion, are independent covariables that influence the clearance of 5FU. Thus, it is conceivable that these factors also play a role in the time of onset of toxicity. The late onset of the clinical symptomatology might also allow sufficient time to apply dose adaptation schedules. Indeed, controlling the AUC by adjusting the dose of 5FU in the middle of a 5-day infusion resulted in a significant decrease in toxicity (24) .
The human DPD gene consists of 23 exons and is at least 950
kb in length, with 3 kb of coding sequence and an average intron size
of about 43 kb (18)
. To date, 14 different mutations have
been identified in the DPD gene, and the vast majority of
these mutations have been detected in patients with a complete DPD
deficiency, which was accompanied by a wide variety in clinical
presentation (12)
. To understand the genetic basis for the
partial DPD deficiency of 14 cancer patients with a reduced DPD
activity, we have analyzed the coding exons of the DPD gene
for the presence of mutations. In this group of patients, six different
mutations were identified including: (a) one splice site
mutation (IVS14+1GA); (b) one missense mutation
(85TC); (c) two polymorphisms (1627AG and 2194GA);
and (d) two novel mutations (496AG and 2846AT).
The missense mutation 85TC has been identified previously in a
homozygous state in two patients with a complete deficiency of DPD, and
a functional analysis of this mutation in Escherichia coli
demonstrated that the C29R mutation resulted in a mutant DPD protein
without significant residual enzyme activity (25)
.
Recently, however, it has been suggested that the C29R mutation might
be a common polymorphism because a high frequency has been noted for
this mutation in a population of cancer patients, including
homozygosity for this mutation in two individuals with almost normal
DPD activity (11)
. The apparent discrepancy between our
results and those reported by Collie-Duguid et al.
(11)
remains enigmatic.
In three patients, no mutations could be detected in the coding
sequences of the DPD gene. We cannot exclude, however, the
possibility that these patients might be heterozygous for a mutation in
the promoter region of the DPD gene. Recently, a
polymorphism that disrupts a putative 
-IFN response element was
identified in a cancer patient with reduced DPD activity
(26)
.
Analysis of the prevalence of the various mutations among cancer
patients with a partial DPD deficiency showed that the GA point
mutation in the invariant splice donor site is the most common one
(43%). This observation is in line with the fact that the IVS14+1GA
mutation is also the most predominant mutation detected in patients
with a complete DPD deficiency (12)
. Surprisingly, the
screening of 23 patients with a reduced DPD activity identified only 1
patient heterozygous for the common splice mutation (11)
.
Our results demonstrate that at least 57% (8 of 14) of the patients
with a reduced DPD activity have a molecular basis for their deficient
phenotype.
In conclusion, a partial DPD deficiency appears to play an important
role in the etiology of 5FU-associated toxicity. Considering the common
use of 5FU in the treatment of cancer patients, the severe 5FU-related
toxicities in patients with a low activity of DPD, and the high
frequency of the IVS14+1GA mutation in DPD-deficient patients, it
would be preferable for the analysis of DPD activity in PBM cells or
screening for the IVS14+1GA mutation to be routinely carried out
before the start of treatment with 5FU.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 To whom requests for reprints should be
addressed, at Academic Medical Center, Laboratory Genetic Metabolic
Diseases, F0-224, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands.
Phone: 31-205665958; Fax: 31-206962596; E-mail: a.b.vankuilenburg{at}amc.uva.nl 
2 The abbreviations used are: 5FU, 5-fluorouracil;
DPD, dihydropyrimidine dehydrogenase; PBM, peripheral blood
mononuclear; AUC, area under the curve.
Received 7/17/00; revised 8/31/00; accepted 9/11/00.
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REFERENCES |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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