Dihydropyrimidine dehydrogenase activity correlates with fluorouracil sensitivity in breast cancer
The fluoropyrimidine drug fluorouracil (FU) is one of the most frequently prescribed chemotherapeutic drugs for the curative and palliative treatment of various cancer patients. The identification of biological factors associated with tumors either responsiveness or resistance to FU chemotherapy, in...
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irk-123456789-1389542018-06-20T03:06:52Z Dihydropyrimidine dehydrogenase activity correlates with fluorouracil sensitivity in breast cancer Yu, Z. Yang, Q. Sun, J. Zhen, J. Original contributions The fluoropyrimidine drug fluorouracil (FU) is one of the most frequently prescribed chemotherapeutic drugs for the curative and palliative treatment of various cancer patients. The identification of biological factors associated with tumors either responsiveness or resistance to FU chemotherapy, including FU, is increasingly being recognized as an important field of clinical cancer research. Aim: to analyze the relationship between intra-tumoral dihydropyrimidine dehydrogenase (DPD) level and FU chemosensitivity, as DPD is the initial and rate-limiting enzyme in the catabolism of FU. Materials and Methods: The histoculture drug response assay (HDRA) was performed for 54 patients. DPD expression was examined in 81 tumor samples from breast cancer patients received two cycles of FU-based primary chemotherapy before operation. Results: We found that intra-tumoral DPD enzyme activity was inversely correlated with FU cytotoxicity. We also revealed that low DPD expression was correlated with clinical response to FU-based primary chemotherapy. Conclusions: Our study indicated that DPD is a promising molecular maker for identifying tumor cells sensitivity in breast cancer patients receiving FU-based chemotherapy. Препарат ряда флуоропиримидина, флуороурацил (FU), является одним из наиболее часто используемых химиотерапевтических препаратов паллиативной терапии больных онкологического профиля. Определение биологических факторов, связанных с чувствительностью либо с устойчивостью опухолей к химиотерапевтическим препаратам, в том числе и к FU, является одним из наиболее важных направлений клинических исследований в онкологии. Цель: проанализировать взаимосвязь между внутриопухолевым уровнем дигидропиримидин дегидрогеназы (DPD) и чувствительностью клеток к FU, поскольку DPD является начальным и лимитирующим энзимом в катаболизме FU. Материалы и методы: определяли чувствительность к препаратам в гистокультуре (histoculture drug response assay, HDRA) у 54 пациентов. Экспрессия гена DPD изучена в 81 образце опухолевой ткани больных раком молочной железы, которым провели два цикла неоадъювантной химиотерапии с применением FU. Результаты: показано, что внутриопухолевая активность DPD обратно коррелирует с цитотоксичностью FU. Также выявлено, что сниженная экспрессия гена DPD коррелиирует с высоким клиническим ответом на первичную химиотерапию, основанную на FU. Выводы: результаты исследования дают основание считать DPD потенциальным молекулярным маркером чувствительности клеток злокачественных опухолей молочной железы к FU. 2007 Article Dihydropyrimidine dehydrogenase activity correlates with fluorouracil sensitivity in breast cancer / Z. Yu, Q. Yang, J. Sun, J. Zhen // Experimental Oncology. — 2007. — Т. 29, № 3. — С. 192–196. — Бібліогр.: 31 назв. — англ. 1812-9269 http://dspace.nbuv.gov.ua/handle/123456789/138954 en Experimental Oncology Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
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Original contributions Original contributions |
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Original contributions Original contributions Yu, Z. Yang, Q. Sun, J. Zhen, J. Dihydropyrimidine dehydrogenase activity correlates with fluorouracil sensitivity in breast cancer Experimental Oncology |
| description |
The fluoropyrimidine drug fluorouracil (FU) is one of the most frequently prescribed chemotherapeutic drugs for the curative and palliative treatment of various cancer patients. The identification of biological factors associated with tumors either responsiveness or resistance to FU chemotherapy, including FU, is increasingly being recognized as an important field of clinical cancer research. Aim: to analyze the relationship between intra-tumoral dihydropyrimidine dehydrogenase (DPD) level and FU chemosensitivity, as DPD is the initial and rate-limiting enzyme in the catabolism of FU. Materials and Methods: The histoculture drug response assay (HDRA) was performed for 54 patients. DPD expression was examined in 81 tumor samples from breast cancer patients received two cycles of FU-based primary chemotherapy before operation. Results: We found that intra-tumoral DPD enzyme activity was inversely correlated with FU cytotoxicity. We also revealed that low DPD expression was correlated with clinical response to FU-based primary chemotherapy. Conclusions: Our study indicated that DPD is a promising molecular maker for identifying tumor cells sensitivity in breast cancer patients receiving FU-based chemotherapy. |
| format |
Article |
| author |
Yu, Z. Yang, Q. Sun, J. Zhen, J. |
| author_facet |
Yu, Z. Yang, Q. Sun, J. Zhen, J. |
| author_sort |
Yu, Z. |
| title |
Dihydropyrimidine dehydrogenase activity correlates with fluorouracil sensitivity in breast cancer |
| title_short |
Dihydropyrimidine dehydrogenase activity correlates with fluorouracil sensitivity in breast cancer |
| title_full |
Dihydropyrimidine dehydrogenase activity correlates with fluorouracil sensitivity in breast cancer |
| title_fullStr |
Dihydropyrimidine dehydrogenase activity correlates with fluorouracil sensitivity in breast cancer |
| title_full_unstemmed |
Dihydropyrimidine dehydrogenase activity correlates with fluorouracil sensitivity in breast cancer |
| title_sort |
dihydropyrimidine dehydrogenase activity correlates with fluorouracil sensitivity in breast cancer |
| publisher |
Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
| publishDate |
2007 |
| topic_facet |
Original contributions |
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http://dspace.nbuv.gov.ua/handle/123456789/138954 |
| citation_txt |
Dihydropyrimidine dehydrogenase activity correlates with fluorouracil sensitivity in breast cancer / Z. Yu, Q. Yang, J. Sun, J. Zhen // Experimental Oncology. — 2007. — Т. 29, № 3. — С. 192–196. — Бібліогр.: 31 назв. — англ. |
| series |
Experimental Oncology |
| work_keys_str_mv |
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| first_indexed |
2025-07-10T06:55:39Z |
| last_indexed |
2025-07-10T06:55:39Z |
| _version_ |
1837242040914542592 |
| fulltext |
192 Experimental Oncology 29, 192–196, 2007 (September)
The fluoropyrimidine drug fluorouracil (FU) is one
of the most frequently prescribed chemotherapeu-
tic drugs for the curative and palliative treatment of
patients with breast, gastrointestinal, head and neck
cancer [1]. The combination of FU with other antican-
cer agents such as cyclophosphamide and metho-
trexate (CMF) has been extensively used for cancer
chemotherapy. Randomized clinical trial revealed that
adjuvant CMF therapy significantly improved overall
survival and relapse-free survival for breast cancer
patients who received CMF therapy compared with
those who did not [2]. Recently, FU based therapy has
been employed in primary neoadjuvant chemotherapy
for patients before breast-conserving treatment
[3, 4]. Successful tumor downstaging by neoadjuvant
chemotherapy has been associated with increased
rates of breast-conserving therapy and shows better
long-term outcomes [5]. Significant variability in the
efficacy of chemotherapy is observed in breast cancer
patients. The sensitivity of cancer drug treatment is
essential for determining the most suitable strategy
for individual cancer patients. However, there are no
standard tools for prediction of a patient’s tumor re-
sponse to chemotherapy.
The identification of molecular factors associated
with either responsiveness or resistance to FU chemo-
therapy is increasingly being recognized as an important
field of study. Dihydropyrimidine dehydrogenase (DPD)
is the initial and rate-limiting enzyme in the catabolism
of FU [6], DPD degrades FU to fluoro-dihydrouracil.
Pharmacokinetic evaluation has further shown that
DPD catabolizes > 80% of and administered dose of
FU, thereby determining the amount of FU available
for anabolism [7]. Early analyses of human tumor cell
xenografts showed a wide range of DPD enzymatic ac-
tivity among various malignant lesions [8–10]. �arious. �arious �arious
human cancer cell line studies demonstrated that DPD
expression is inversely correlated with FU response [11,
12]. Animal study revealed that human tumor xenografts
expressing low levels of DPD mRNA and DPD activity
showed a significantly better response to FU than tu-
mors with high DPD mRNA level of DPD activity [13].
These basic studies suggested that the intra-tumoral
levels of DPD may be an important factor for predicting
the response of clinical tumors to FU.
�ery few studies have investigated the relationship
between DPD expression/activity and the effect of FU
based chemotherapy for primary gastric cancer, and
the conclusions are still controversial [14–16]. We
assume that the controversial results may be partially
due to bias from treatment strategy including sur-
gery and postoperative adjuvant radio- or hormonal
treatment. To exclude the surgical and postoperative
interventions, we performed two prospective studies:
(A) The histoculture drug response assay (HDRA) [17]
was performed for surgically resected fresh breast
tumor, intra-tumoral DPD activity was assessed and
DIHYDROPYRIMIDINE DEHYDROGENASE ActIvItY cORRELAtES
WItH FLuOROuRAcIL SENSItIvItY IN BREASt cANcER
Z. Yu1, *, Q. Yang2, 3, *, J. Sun2, J. Zhen4
1Department of Breast Surgery, the Second Affiliated Hospital of Shandong University, �i�nan, Shandong�i�nan, Shandong
Province, People�s Republic of China
2Department of Breast Surgery, �ilu Hospital of Shandong University, �i�nan, Shandong Province,Breast Surgery, �ilu Hospital of Shandong University, �i�nan, Shandong Province,Surgery, �ilu Hospital of Shandong University, �i�nan, Shandong Province,
People�s Republic of China
3The Cancer Institute of New �ersey, UMDN�-Robert Wood �ohnson Medical School, New Brunswick, N�
08903, USA
4Department of Pathology, Shandong University, �i�nan, Shandong Province, People�s Republic of China
The fluoropyrimidine drug fluorouracil (FU) is one of the most frequently prescribed chemotherapeutic drugs for the curative and
palliative treatment of various cancer patients. The identification of biological factors associated with tumors either responsiveness
or resistance to FU chemotherapy, including FU, is increasingly being recognized as an important field of clinical cancer research.
Aim: to analyze the relationship between intra-tumoral dihydropyrimidine dehydrogenase (DPD) level and FU chemosensitivity,
as DPD is the initial and rate-limiting enzyme in the catabolism of FU. Materials and Methods: The histoculture drug response
assay (HDRA) was performed for ��� patients. DPD e�pression was e�amined in ��� tumor samples from breast cancer patients��� patients. DPD e�pression was e�amined in ��� tumor samples from breast cancer patients patients. DPD e�pression was e�amined in ��� tumor samples from breast cancer patients��� tumor samples from breast cancer patients tumor samples from breast cancer patients
received two cycles of FU-based primary chemotherapy before operation. Results: We found that intra-tumoral DPD enzyme activ-
ity was inversely correlated with FU cytoto�icity. We also revealed that low DPD e�pression was correlated with clinical responseinversely correlated with FU cytoto�icity. We also revealed that low DPD e�pression was correlated with clinical responsecorrelated with FU cytoto�icity. We also revealed that low DPD e�pression was correlated with clinical responselow DPD e�pression was correlated with clinical responseDPD e�pression was correlated with clinical response
to FU-based primary chemotherapy. Conclusions: Our study indicated that DPD is a promising molecular maker for identifying
tumor cells sensitivity in breast cancer patients receiving FU-based chemotherapy.receiving FU-based chemotherapy.FU-based chemotherapy.
Key Words: fluorouracil, dihydropyrimidine dehydrogenase, breast cancer, chemosensitivity.
Received: July 3, 2007.
Correspondence: Zhigang Yu
Fax: +86-531-88960949
E-mail: yzg@medmail.com.cn
Qifeng Yang
E-mail: qifengy@gmail.com
Abbreviations used: FU — fluorouracil; DPD — Dihydropyrimidine
dehydrogenase; HDRA — histoculture drug response assay; PBS —
phosphate-buffered saline; DMSO — dimethyl sulfoxide.
Exp Oncol 2007
29, 3, 192–196
Experimental Oncology 29, 192–196, 2007 (September) 19329, 192–196, 2007 (September) 193September) 193) 193 193
compared with FU HDRA chemosensitivity; (B) Clinical
response was evaluated for a cohort of breast cancer
patients received two cycles of FU based primary
chemotherapy before operation, DPD expression was
compared with FU-based chemosensitivity.
MAtERIALS AND MEtHODS
Patients and samples. Two groups of operable
primary invasive breast carcinomas were included in our
current in �i����i������ and in �i�� FU chemosensitivity studies.
The in vitro group consisted of 54 invasive ductal carcino-54 invasive ductal carcino- invasive ductal carcino-
mas. None of the patients received chemotherapy or ir-
radiation therapy prior to the surgery. Surgically resected
breast cancer tissues were quickly divided into three
samples: one was fixed in 10% buffered formaldehyde for
pathological diagnosis, one was submitted for DPD en-
zyme activity measurement, and one for HDRA [17]. The
in �i�� group consisted of 81 invasive ductal carcinomas
enrolled in a clinical trial. Before operation, core needleBefore operation, core needle
biopsy was performed to obtain tissue for pathological
diagnosis and immunohistochemistry analysis, and allll
patients were scheduled to two cycles of CMF treatment.
All tumor samples were collected with consent for tissue
donation and local research ethics committee approval
for use of the tissue surplus to diagnostic requirements
for cellular and molecular assays.
Measurement of DPD enzyme activity. DPD
activity was determined using a catalytic assay accord-
ing to the method described by Ikenaka et al. [7] with
modification. Breast cancer tissues were homogenized
in four volumes of 50 mM of Tris-HCl (pH 8.0) containing
5 mM of 2-mercaptoethanol, 25 mM of KCl, and 5 mM
of MgCl2. After homogenization, the sample was centri-
fuged at 105,000 g for 60 min at 4 °C. The supernatant
cytosol layer was collected as the enzyme source for the
measurement of DPD activity. Microspin G-25 column
(Amersham Biosciences, Piscataway, NJ) was used to
remove internal substrate including racil and thymine.
The remaining cytosolic fraction was frozen and stored
at –80 °C until analysis. The assay mixture (0.25 ml)
consisted of 50 mM Tris-HCl (pH 8.0), 10 mM MgCl2, 25
mM NaF, 50 mM nicotinamide, 5 mM ATP, 1 mM NADPH,
[6-3H] 5-FU (0.2 mCi, 20 mM), and 0.1 ml of the enzyme
extract. The mixture was incubated for 30 min at 37 °C,
and the reaction was stopped by heating at 100 °C in a
water bath. After centrifugation at 3000 rpm, the su-
pernatant (0.1 ml) was treated with 0.01 ml of 2M KOH
for 30 min at room temperature. Then, the mixture was
treated with 0.005 ml of 2M PCA and centrifuged. A 20ml
aliquot of the supernatant was taken and spotted onto
a thin-layer chromatography plate (Merck, Whitehouse
Station, NJ) and developed with a mixture of chloroform,
methanol, and acetic acid (17 : 3 : 1, v/v/v). The spots
of 2-fluoro-alanine and 2-fluoro-ureidopropionic acid,
FU degradation products, were scraped into vials and
mixed with 10 mL of ACS-II scintillation fluid (Amersham,
Buckinghamshire, UK). The radioactivity was measured
in a Wallac 1410 liquid scintillation counter (Pharmacia,
Uppsala, Sweden). Internal controls were used to com-
pare assays.
Immunohistochemistry. For the immunohisto-
chemical study, 4 µm thick sections on silane-coated
slides were dewaxed with xylene and rehydrated
through a graded alcohol series. Then, endogenous
peroxidase activity was blocked in absolute methanol
solution containing 0.3% hydrogen peroxide for 35 min
and the slides were washed in 10 mM phosphate-buffe-
red saline (PBS), pH 7.4. For antigen retrieval, they
were immersed in 1mm citrate-phosphate buffer, and
microwaved at 100 °C for 15 min. After the buffer had
cooled, 10% fetal serum was reacted with the slides
for 15 min to eliminate non-specific immunostaining.
The sections were then incubated with anti-DPD poly-
clonal antibodies [18] overnight at 4 °C in a humidified
chamber. Biotinylated goat anti-rabbit IgG was applied
as a secondary antibody for 20 min at room tempera-
ture, followed by streptavidin-biotinylated peroxidase
complex for 20 min at room temperature. Peroxidase
activity was visualized with a diaminobenzidine as the
chromogen. Replacement of the primary antibody with
PBS was used as a negative control. Immunoreactivity
in the cytoplasm of cancer cells was observed to evalu-
ate DPD. When more than 25% of the cancer cells were
stained, the specimen was defined as positive.
HDRA. HDRA was conducted according to previous
report [19]. Briefly, FU was dissolved in RPMI-1640
medium (Sigma, St. Louis, MO) containing 20% fetal
bovine serum (FCS, lansa, Mexico), penicillin-strep-
tomycin-amphotericin B (Gibco; 100 IU/ml, 100 µg/ml
and 0.25% µg/ml, respectively), and 1 ml solution
per well was poured onto a 24-well palate. The cutoff
concentration used to distinguish in �i��� sensitivity and
resistance was 300 µg/ml, which was appropriate to
the plasma level achieved in �i�� [19]. After the incuba-
tion for 7 days, 100 µl of 0.2% MTT (Sigma)/phosphate
buffered saline (PBS) solutions, containing 50 mM
sodium succinate, was added to each well. After the
plates were incubated for a further 16 h, the medium
was removed from each well, and 0.5 ml dimethyl
sulfoxide (DMSO) per well was added to extract MTT-
formazan. After 2 h, 100 µl solution was extracted from
each well, transferred to 96-well multiplate, and their
absorbance was read by microplate reader at 540 nm
with a reference of 630 nm. The inhibition index (I.I.)
was calculated using the formula: I.I. = (1-T/C) x 100,
where T is mean absorbency of the treated wells per
1 g tumor, and C is mean absorbance of the control
wells per 1 g tumor. As reported previously, the cut-off
I.I. of 60% was employed for our study [20].
FU-based chemotherapy and evaluation. Two
cycles of CMF (cyclophosphamide, methotrexate and
fluorouracil) were used for patients in this group. Tumor
response was determined by palpation after two cycles of
treatment. If the tumor size decreased less than 50%, pa-
tients was evaluated as resistante to the chemotherapy, if
the tumor size decreased more than 50%, the response
were defined as sensitive to the treatment.
Statistical analysis. A computer program package
(Stat�iew 5.0, Abacus Concepts, Berkeley, CA, USA)
was used for all statistical testing and management of
194 Experimental Oncology 29, 192–196, 2007 (September)
the database. Non-parametric Mann — Whitney U-test
was used to compare median values between sensi-
tive and resistant groups for in vitro chemosensitivity
study. For in vivo study, chi-square test was used to
test the relationship between DPD expression and
FU-based chemosensitivity. A p-value less than 0.05
was considered statistically significant.
RESuLtS
Association between in vitro FU chemosen-
sitivity and DPD Enzyme Activity. With the cut-
off I.I. of 60%, 18 out of the 54 (33.33%) patients
were sensitive to FU. The DPD enzyme activity was
56.11 ± 8.45 in the chemosensitive group, and 77.44 ±
5.97 pmol/mg per min in the chemoresistant group. As
shown in Fig. 1, DPD enzyme activity was significantly
lower in the sensitive group than resistant group (p <
0.0442).
Fig. 1. Correlation between intratumoral DPD activity and FU
in �i��� chemosensitivity
Association between in vivo FU-based chemo-
sensitivity and DPD expression. With two cycles
of CMF chemotherapy, 39 out of 81 (48.15%) tumors
were evaluated to be sensitive to the treatment and 42
(51.85%) were resistant. According to immunostain-
ing, 44 out of 81 (54.32%) tumors were evaluated as
immunopositive for DPD, and 37 (45.68%) were im-
munonegative (Fig. 2). As shown in Table, the tumors
with positive DPD expression were resistant to FU, and
the tumors with low DPD expression were sensitive to
FU (p < 0.0001).
Fig. 2. Immunohistochemical staining of breast cancers using
anti-DPD polyclonal antibody. The tumor cells showed diffuse
cytoplasm staining for anti-DPD (x 400)
Table. Relationship between DPD expression and response to FU-based
chemotherapy
DPD In vivo chemosensitivity
sensitive resistant p value
Negative 29 8 < 0.0001
Positive 10 34
DIScuSSION
Chemotherapy is one of the extremely effective mo-
dalities of breast cancer therapy before and/or after op-
eration. No single regimen has been demonstrated to be
effective in 100% of patients even with the same tumor
type. Accurate prediction of an individual patient’s drug
response is an important prerequisite of personalized
medicine. Therefore, there is a great need to identify
biological marker(s) that can predict response or re-
sistance to chemotherapy [21]. FU is one of the most
frequently prescribed chemotherapeutic drugs.
The HDRA may be an appropriate method for the cul-
ture of breast cancer since it allows the interstitial cells,
which occupy the major portion of the tumor in breast
cancer, to be cultured in their natural three-dimensional
architecture with the cancer cells [22]. The HDRA che-
mosensitivity results predict clinical outcomes with high
sensitivity in cancers of head and neck, stomach, colon,
urinary tract, ovary, and breast [23–28]. In the present
study, HDRA was performed on 54 samples. DPD ac-
tivity was measured by using a catalytic assay [7]. We
correlated the result of FU sensitivity in HDRA and DPD
activity in tumor tissue and found that decreased DPD
activity was associated with FU sensitivity. Our result is
consistent with the finding from a previous study [20].
We further analyzed if intra-tumoral DPD expression was
correlated with in �i�� chemosensitivity in 81 patients
who received two cycles of FU-based chemotherapy.
As the results, decreased DPD expression was closely
related with the early response to preoperative chemo-
therapy. Prediction of treatment effect might help to
exclude patients with a low probability of a treatment
benefit and improve the benefit/risk ratio in breast
cancer patients receiving neoadjuvant chemotherapy.
Based on our current study, DPD may be a promising
molecular maker to identify patients with lower DPD
expression for FU-based chemotherapy.
Interestingly, there were shown different modes of
action of FU-based drugs (tegafur + uracil [UFT], tega-
fur + gimeracil + oteracil [S-1], 5'-deoxy-5-fluorouri-
dine [5'-DFUR], and N4-pentyloxycarbonyl-5'-deoxy-
5-fluorocytidine [capecitabine]), as well as three other
drugs (cisplatin [CDDP], irinotecan hydrochloride
[CPT-11], and paclitaxel) on genes expression pro-
files which correlated with the sensitivity of 30 human
tumor xenografts in the recent study [29]. DPD mRNA
expression profiles of the tumors showed a significant
negative correlation with chemosensitivity to all of the
FU based drugs except for S-1. S-1 has recently been
developed, which consists of tegafur (FT), 5-chloro-2,
4-dihydroxypyridine (CDHP), and potassium oxonate
(Oxo) in a molar ratio of 1 : 0.4 : 1. FT is a prodrug of FU,
and CDHP competitively inhibits DPD about 180 times
more effectively than uracil, and leads to the retention
Experimental Oncology 29, 192–196, 2007 (September) 19529, 192–196, 2007 (September) 195September) 195) 195 195
of a prolonged concentration of FU [30]. Therefore, the
administration of S-1 might be an effective strategy for
the treatment of high DPD-expressing tumors [31].
In conclusion, we analyzed the relationship between
the DPD activity and the sensitivity to in �i��� and in �i��
FU chemosensitivity. We found that the basal level of
DPD expression/activity was significantly correlated
with FU sensitivity in primary breast cancer. DPD is a
promising molecular marker for identifying patients for
FU-based and/or s-1 based chemosensitivity.
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активность ДиГиДРоПиРиМиДин ДЕГиДРоГЕнаЗЫ
коРРЕЛиРУЕт с ЧУвствитЕЛьностьЮ к фЛУоРоУРациЛУ
ПРи РакЕ МоЛоЧноЙ ЖЕЛЕЗЫ
Препарат ряда флуоропиримидина, флуороурацил (FU), я�ляет�я одним и�� наи�олее �а�то и�пол���уем��� ��имиоте-FU), я�ляет�я одним и�� наи�олее �а�то и�пол���уем��� ��имиоте-), я�ляет�я одним и�� наи�олее �а�то и�пол���уем��� ��имиоте-
рапе�ти�е�ки�� препарато� паллиати�ной терапии �ол�н��� онкологи�е�кого профиля. Определение �иологи�е�ки��
факторо�, ��я��анн��� � �у��т�ител�но�т�ю ли�о � у�той�и�о�т�ю опу��олей к ��имиотерапе�ти�е�ким препаратам,
� том �и�ле и к FU, я�ляет�я одним и�� наи�олее �а�н��� напра�лений клини�е�ки�� и��ледо�аний � онкологии.FU, я�ляет�я одним и�� наи�олее �а�н��� напра�лений клини�е�ки�� и��ледо�аний � онкологии., я�ляет�я одним и�� наи�олее �а�н��� напра�лений клини�е�ки�� и��ледо�аний � онкологии.
Цель: проанали��иро�ат� ���аимо��я��� ме�ду �нутриопу��оле��м уро�нем дигидропиримидин дегидрогена��� (DPD)DPD))
и �у��т�ител�но�т�ю клеток к FU, по�кол�ку DPD я�ляет�я на�ал�н�м и лимитирую�им �н��имом � ката�оли��меFU, по�кол�ку DPD я�ляет�я на�ал�н�м и лимитирую�им �н��имом � ката�оли��ме, по�кол�ку DPD я�ляет�я на�ал�н�м и лимитирую�им �н��имом � ката�оли��меDPD я�ляет�я на�ал�н�м и лимитирую�им �н��имом � ката�оли��ме я�ляет�я на�ал�н�м и лимитирую�им �н��имом � ката�оли��ме
FU.. Материалы и методы: определяли �у��т�ител�но�т� к препаратам � ги�токул�туре (histoculture drug responsehistoculture drug response drug responsedrug response responseresponse
assay, HDRA) у ��� пациенто�. �к�пре��ия гена, HDRA) у ��� пациенто�. �к�пре��ия генаHDRA) у ��� пациенто�. �к�пре��ия гена) у ��� пациенто�. �к�пре��ия гена DPD и��у�ена � ��� о�ра��це опу��оле�ой ткани �ол�н��� раком моло�ной
�еле���, котор�м про�ели д�а цикла неоадъю�антной ��имиотерапии � применением FU.FU.. Результаты: пока��ано, �то
�нутриопу��оле�ая акти�но�т� DPD о�ратно коррелирует � цитоток�и�но�т�ю FU. �ак�е ��я�лено, �то �ни�еннаяDPD о�ратно коррелирует � цитоток�и�но�т�ю FU. �ак�е ��я�лено, �то �ни�енная о�ратно коррелирует � цитоток�и�но�т�ю FU. �ак�е ��я�лено, �то �ни�еннаяFU. �ак�е ��я�лено, �то �ни�енная. �ак�е ��я�лено, �то �ни�енная
�к�пре��ия гена DPD коррелиирует � ���оким клини�е�ким от�етом на пер�и�ную ��имиотерапию, о�но�анную
на FU.FU.. Выводы: ре��ул�тат� и��ледо�ания дают о�но�ание ��итат� DPD потенциал�н�м молекулярн�м маркеромDPD потенциал�н�м молекулярн�м маркером потенциал�н�м молекулярн�м маркером
�у��т�ител�но�ти клеток ��лока�е�т�енн��� опу��олей моло�ной �еле��� к FU.FU..
Ключевые слова: флуороурацил, дигидропиримидин дегидрогена��а, рак моло�ной �еле���, �у��т�ител�но�т� к
��имиотерапии.
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