close

Вход

Забыли?

вход по аккаунту

?

847

код для вставкиСкачать
1626
High Expression of Thymidylate Synthase Is
Associated with the Drug Resistance of Gastric
Carcinoma to High Dose 5-Fluorouracil–Based
Systemic Chemotherapy
Kun-Huei Yeh, M.D.1,5,6
Chia-Tung Shun, M.D.3
Chi-Long Chen, M.D., Ph.D.3
Jaw-Town Lin, M.D., Ph.D.2
Wei-Jei Lee, M.D., Ph.D.4
Po-Huang Lee, M.D., Ph.D.4
Yao-Chang Chen, M.D.1,2,5
Ann-Lii Cheng, M.D., Ph.D.1,2,5
BACKGROUND. In the past 4 years, the weekly 24-hour infusion of high dose 5-
1
Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan, Republic of
China.
2
Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan, Republic of China.
3
Department of Pathology, National Taiwan
University Hospital, Taipei, Taiwan, Republic of
China.
4
Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan, Republic of
China.
5
Cancer Research Center, National Taiwan University College of Medicine, Taipei, Taiwan, Republic of China.
6
fluorouracil (5-FU) and leucovorin in the treatment of patients with advanced
gastric carcinoma has been prospectively studied at the authors’ institution. This
has enabled them to explore the possibility that the level of expression of thymidylate synthase (TS), the target enzyme of 5-FU, is related to the drug sensitivity of
gastric carcinoma to 5-FU–based chemotherapy.
METHODS. To be eligible for this study, patients were required to have received
high dose 5-FU and leucovorin chemotherapy (weekly 24-hour infusions of 5-FU,
2,600 mg/m2, and leucovorin, 300 mg/m2) and to have had adequate prechemotherapy gastric carcinoma tissues for immunohistochemical study. TS106 monoclonal antibody was used to detect the expression of TS. A visual scoring system,
which ranged from 0 to 3/, was adopted by 2 independent pathologists to semiquantitate the intensity of TS expression.
RESULTS. Between 1993 and 1996, a total of 30 patients, 18 men and 12 women,
with a median age of 61.5 years, were enrolled. Of these patients, 16 (53.3%) and
14 (46.7%) had high and low expression of TS, respectively. Two of the 16 patients
(12.5%) with high expression of TS and 13 of the 14 patients (92.9%) with low
expression of TS responded to chemotherapy (P õ 0.001, chi-square test). The
median overall survival was 10 months for patients with low TS expression and 4
months for patients with high TS expression (P õ 0.01, log rank test).
CONCLUSIONS. The data from this study suggest that the expression of TS, as
determined by immunohistochemistry, is a relatively reliable indicator of whether
5-FU should be used in the treatment of patients with gastric carcinoma. Cancer
1998;82:1626–31. q 1998 American Cancer Society.
Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine,
Taipei, Taiwan, Republic of China.
KEYWORDS: thymidylate synthase, 5-fluorouracil, drug resistance, gastric carcinoma.
Presented in part as a poster at the 88th annual
meeting of the American Association for Cancer
Research, San Diego, California, April 12–16,
1997; the material presented was published in
Proc Am Assoc Cancer Res 1997;38:99 (abstract 664).
G
Supported by a grant from National Taiwan University Hospital (NTUH-85142-A02), a grant
from the National Science Council (NSC862314-B-002-178), and a core grant for the Cancer Research Center of National Taiwan University College of Medicine from the Department
astric carcinoma is one of the leading causes of cancer-related
death around the world.1,2 More than two-thirds of patients with
of Health (DOH85-HR-525), Taiwan, Republic
of China.
The authors thank Dr. Patrick G. Johnston (Division of Cancer Treatment, Navy Medical Oncology Branch, National Cancer Institute, Bethesda,
Maryland) for providing monoclonal antibody
TS106.
q 1998 American Cancer Society
/ 7bc2$$1089
04-10-98 14:21:22
canxa
W: Cancer
Address for reprints: Ann-Lii Cheng, M.D.,
Ph.D., Department of Internal Medicine, National Taiwan University Hospital, No. 7, ChungShan South Road, Taipei, Taiwan, Republic of
China, 100.
Received July 10, 1997; revision received November 7, 1997; accepted November 7, 1997.
TS Expression and 5-FU Resistance in Gastric Carcinoma/Yeh et al.
this disease are diagnosed in advanced stages, for
which curative surgery plays only a limited role.2,3
Within months or years, the majority of gastric carcinoma patients enter a phase of far-advanced disease,
for which systemic chemotherapy is the only effective
palliative treatment.4,5
Gastric carcinoma is moderately sensitive to chemotherapy.4,5 In the past decade, we6 – 8 and other investigators9 – 11 have developed new chemotherapy
protocols that yielded tumor remission rates of approximately 50 – 70% in selected patients with advanced gastric carcinoma. Although the remission rate
improved, the duration of remission remained relatively short; hence, overall survival was not remarkably
prolonged. The brief response to chemotherapy was
most likely the consequence of a rapid emergence of
drug resistance. However, the nature and molecular
mechanisms of the drug resistance of gastric carcinoma cells remain largely unknown. Preliminary data
have suggested that certain drug-resistance molecules
may have played important roles in this scenario.12,13
Because most chemotherapy protocols contain multiple drugs with different mechanisms of action, a clear
association between a drug-resistance marker and an
anticancer drug is hard to establish. In the past 4 years,
we have been testing the efficacy of a treatment protocol for advanced gastric carcinoma that involves a
weekly high dose infusion of 5-fluorouracil (5-FU).8
This has enabled us to determine whether the expression of thymidylate synthase (TS), the target enzyme
of 5-FU,14,15 may predict drug resistance of gastric carcinoma cells to 5-FU.
MATERIALS AND METHODS
Patients, Chemotherapy, and Clinical Trials
To be eligible for this study, the patients were required
to 1) have a tissue diagnosis of gastric adenocarcinoma, 2) have received high dose 5-FU and leucovorin
(HDFL) chemotherapy according to a clinical trial protocol that consisted of a weekly 24-hour infusion of 5FU (2600 mg/m2) plus leucovorin (300 mg/m2), 3) have
complete clinical information, and 4) have adequate
prechemotherapy gastric carcinoma tissues for immunohistochemical study of TS.
The details of the clinical trials have been described previously.8 Physical examination, complete
blood count, and serum biochemistry were checked
every 1 – 2 weeks. Indicator lesions were evaluated at
least every 4 – 8 weeks by physical examination, X-ray,
ultrasonography, upper gastrointestinal panendoscopy, and computed tomography (CT) scan. When
documentation of response was required, the indicated studies were repeated within 1 month. Carcinoembryonic antigen (CEA), if elevated before treat-
/ 7bc2$$1089
04-10-98 14:21:22
1627
ment, was studied monthly. However, CEA or other
tumor markers were not used as the sole parameters
for assessing treatment response. Whole-body bone
scans and other examinations were performed when
indicated.
Complete remission (CR) of the tumors was defined as complete disappearance of all lesions, without
appearance of any new lesions, for at least 4 weeks.
Partial remission (PR) was defined as a decrease of
50% of the sum of the products of the greatest perpendicular dimensions of all measurable lesions, without
the appearance of any new lesions, for at least 4 weeks.
Progressive disease (PD) was defined as an increase of
greater than 25% in the sum of the products of the
greatest perpendicular dimensions of all measurable
lesions or the development of new lesions. Worsening
of tumor-related symptoms in patients with stable disease was also documented as PD. All other patients
were considered to have stable disease (SD). In this
study, ‘‘responders’’ were patients who achieved either partial response (PR) or complete response (CR),
and ‘‘non-responders’’ were patients who had stable
disease (SD) or progressive disease (PD) during chemotherapy.
Immunohistochemical Staining for Thymidylate Synthase
Tumor specimens were obtained by either surgical resection or biopsy of primary or metastatic gastric carcinoma. For immunohistochemical studies, formalin
fixed, paraffin embedded tissues were cut into sections
6 mm in thickness. Tissue sections were deparaffinized
in xylene after being heated on a hot plate, rehydrated
in graded alcohol, and washed in phosphate-buffered
saline (PBS).
For semiquantitative study of the expression of
TS, the specific monoclonal antibody TS106 was used
for immunohistochemical staining. TS10616,17 (kindly
provided by Dr. Patrick G. Johnston, Division of Cancer Treatment, Navy Medical Oncology Branch, National Cancer Institute, Bethesda, MD), which defines
TS, was used.
Sections were treated with 3% hydrogen peroxide
in methanol at room temperature for 30 minutes to
block endogenous peroxidase, then sections were incubated with TS106 in a moist chamber at 4 7C. The
incubation time for TS106 was 60 minutes. The sections were then stained by the avidin-biotin-complex
(ABC) peroxidase method18 with a commercially available kit, the ZYMED Labeled – [Strept]Avidin-Biotin
(LAB-SA) System (ZYMED Laboratories Inc., South San
Francisco, CA), according to the manufacturer’s instructions. Finally, sections were counterstained with
methyl green and mounted.
Formalin fixed, paraffin embedded sections of a
canxa
W: Cancer
1628
CANCER May 1, 1998 / Volume 82 / Number 9
FIGURE 1. In this study, the visual grading system for immunohistochemical stains with TS106 monoclonal antibody graded tumor tissues as
having intensity 0 (A), intensity 1/ (B), intensity 2/ (C), or intensity 3/ (D) (original magnification 1400).
colon adenocarcinoma known to have high expression
of TS were used as positive controls for TS. Negative
controls, to which the primary antibodies were not
applied, were processed step-by-step with each experiment. During each run of immunohistochemical
staining, the same positive and negative controls were
used; they served to standardize the intensity of expression in the gastric carcinoma specimens.
Semiquantitative Analysis of Immunohistochemical
Staining
Immunostained slides were examined independently
by 2 pathologists (C. T. Shun and C. L. Chen) who
were not informed of the clinical information. TS106
immunostaining was semiquantitated by a visual
grading system in which the intensity of staining was
categorized as 0, 1/, 2/, or 3/; this was similar to the
grading system originally defined by Johnston et al.19
(Fig. 1). Intensity 0 was defined as a total absence of
TS immunostaining. Intensity 1/ was defined as less
than 25% of tumor staining positive, or only faint
staining, compared with the positive controls. Intensity 2/ was defined as 25 – 50% of tumor staining posi-
/ 7bc2$$1089
04-10-98 14:21:22
tive, or moderate staining, compared with the positive
controls. Intensity 3/ was defined as more than 50% of
tumor staining positive, or strong staining, compared
with the positive controls.
Statistical Analysis
The statistical significance of differences between response and various clinicopathologic features was assessed by the chi-square test or Fisher’s exact test.
Patients’ survival data were analyzed by the Kaplan –
Meier estimation method.20 Differences between individual survival curves were evaluated by the log rank
test.21 Differences in patients’ ages were evaluated by
the Mann – Whitney rank sum test.22
RESULTS
Patient Characteristics
Between 1993 and 1996, a total of 30 patients, 18 men
and 12 women, with a median age of 61.5 years (range,
32 – 78 years), were enrolled onto this study. There
were 15 responders and 15 nonresponders to HDFL
chemotherapy. All 15 responders achieved PR. One
patient had previously received adjuvant chemother-
canxa
W: Cancer
TS Expression and 5-FU Resistance in Gastric Carcinoma/Yeh et al.
1629
TABLE 1
Pertinent Clinicopathologic Features of the Patients
No. of patients
Gender (male/female)
Median age, yrs (range)
KPS
¢70%
60–69%
50–59%
40–49%
30–39%
Status of disease
Primary nonresectable
Locally advanced
Metastatic
Postgastrectomy
Local recurrence
Metastatic
Elevated CEA (¢3 ng/mL)
Prior chemotherapy
Histopathology
Diffuse type
Intestinal type
Responders
High TS
expression
Low TS
expression
P valuea
16
7/9
61.5 (32–78)
14
11/3
61.5 (42–77)
—
NS
NS
12 (75.0%)
0 (0.0%)
1 (6.25%)
1 (6.25%)
2 (12.5%)
8 (57.1%)
2 (14.3%)
2 (14.3%)
1 (7.1%)
1 (7.1%)
NS
NS
NS
NS
NS
1 (6.25%)
6 (37.5%)
3 (21.4%)
6 (42.9%)
NS
NS
1 (6.25%)
8 (50.0%)
10 (62.5%)
1 (6.25%)
0 (0.0%)
5 (35.7%)
6 (42.9%)
0 (0.0%)
NS
NS
NS
NS
6 (37.5%)
10 (62.5%)
2 (12.5%)
8 (57.1%)
6 (42.9%)
13 (92.9%)
NS
NS
õ0.001
TS: thymidylate synthase; KPS: Karnofsky performance status; CEA: carcinoembryonic antigen; NS: not statistically significant.
a
P values were calculated by the chi-square test or Fisher’s exact test.
apy consisting of 5-FU, doxorubicin, and mitomycin
C (FAM),23 which was completed 11 months before
HDFL chemotherapy was given. The other 29 patients
were chemo-naive. There was no significant difference
in the pertinent clinicopathologic features between
the patients with high TS expression and those with
low TS expression (Table 1).
Correlation of High Thymidylate Synthase Expression
with Resistance to 5-Fluorouracil
‘‘Low’’ expression and ‘‘high’’ expression were defined
as intensity 0 and 1/ and as intensity 2/ and 3/,
respectively. There was close agreement (of 90.0%) between the TS evaluations of the 2 pathologists. In the
3 cases of disagreement between intensity 1/ and 2/,
the final grading was determined by consensus between the 2 pathologists.
The percentage of patients with high expression
of TS106 was 53.3% (16 of 30). Two of 16 patients
(12.5%) with high expression of TS and 13 of 14 patients (92.9%) with low expression responded to chemotherapy (P õ 0.001 by the chi-square test, 16.205
with 1 degree of freedom) (Table 1).
Four of 5 patients (80%) with intensity 0 and 9
of 9 patients (100%) with intensity 1/ of TS staining
/ 7bc2$$1089
04-10-98 14:21:22
responded to HDFL treatment (P Å 0.357 by Fisher’s
exact test). On the other hand, 1 of the 10 (10%) with
intensity 2/ and 1 of the 6 (16.7%) with intensity 3/
of TS staining responded to HDFL treatment (P Å
1.000 by Fisher’s exact test) (Fig. 2).
The median overall survival was 10 months for
patients with low TS expression and 4 months for patients with high TS expression (P Å 0.009 by the logrank test) (Fig. 3).
DISCUSSION
Continuous infusion of 5-FU was recently recognized
as an effective treatment for advanced gastric carcinoma.24 Incorporation of 5-FU and its biochemical
modulator, leucovorin (LV), has previously been tried
in the treatment of gastric carcinoma with various degrees of success.25,26 Recently, we demonstrated that
the HDFL regimen, in which high dose 5-FU (2600
mg/m2/week) and leucovorin (300 – 500 mg/m2/week)
were administered by weekly 24-hour infusion, is an
effective treatment for advanced gastric carcinoma
with minimal toxicity.8
Expression of TS, the target enzyme of 5-FU,14,15
has previously been demonstrated to be associated
with chemoresistance to 5-FU – based chemotherapy
canxa
W: Cancer
1630
CANCER May 1, 1998 / Volume 82 / Number 9
FIGURE 2. Response rates (%) to high dose 5-fluorouracil and leucovorin treatment are shown, according to the distribution of thymidylate
synthase (TS) staining intensity.
FIGURE 3.
Kaplan–Meier curves of overall survival for patients with
high thymidylate synthase (TS) expression (n Å 6) and those with low
TS expression (n Å 4) are shown.
series of 30 prospectively studied patients is the largest
to date. Our data confirmed that the high expression
of TS in gastric carcinoma is associated with drug resistance to 5-FU chemotherapy.
Although the correlation was highly significant, TS
expression may not be the only mechanism responsible for 5-FU resistance in gastric carcinoma cells. For
example, one patient with low TS expression in our
series was resistant to HDFL treatment. On the other
hand, 2 patients with high TS expression in our series
had good responses to HDFL treatment. One possible
explanation for the good responses is that the amino
acid sequence of TS protein might have been mutated.29 This might have led to high TS expression on
immunohistochemical staining but low TS enzyme activity. This possibility must be explored further.
In addition, there is always the possibility that TS
expression is only one of the biologic markers reflecting a more generalized phenomenon of drug resistance. For example, five of our patients with high TS
expression also had samples stain positively for multidrug resistance-1 (MDR-1) protein (data not shown),
which was theoretically unrelated to 5-FU resistance.
These seemingly unrelated mechanisms, including
MDR-1 expression,30 protein kinase C (PKC) signal
transduction pathway,30 stress-activated protein kinase/Jun N-terminal kinase,31,32 and NF-erkB transcriptional factor,33 may represent part of a global antistress response of the cells. It would be intriguing to
investigate further the possibility that TS fits into this
generalized defense system of the cancer cells.
In conclusion, our data indicated that TS is an
important marker for predicting the chemosensitivity
of gastric carcinoma cells to 5-FU. If 5-FU-alone regimens (such as HDFL) are used, prechemotherapy immunohistochemical staining for TS will be a relatively
reliable method for selecting patients who will respond
satisfactorily. If high TS expression is detected, the use
of other therapeutic agents, such as cisplatin, doxorubicin, and etoposide, is advisable.
REFERENCES
1.
in colorectal19,27 and gastric carcinoma.27,28 However,
studies of gastric carcinoma have been limited by either the involvement of a small number of patients or
the use of multiple agents in the treatment protocols.
For example, the study of Johnston et al. included only
12 gastric carcinoma patients,27 and the study of Lenz
et al. used cisplatin and 5-FU in the treatment of gastric carcinoma.28 Because our study used high dose 5FU only, we were able to establish a clear-cut correlation between TS expression and 5-FU resistance in
gastric carcinoma. Furthermore, to our knowledge, our
/ 7bc2$$1089
04-10-98 14:21:22
2.
3.
4.
5.
canxa
Boeing H. Epidemiological research in stomach cancer:
progress over the last ten years. J Can Res Clin Oncol
1991;117:133–43.
Fuchs CS, Mayer RJ. Gastric carcinoma. N Engl J Med
1995;333:32–41.
Cunningham D, Hole D, Taggart DJ, Soukop M, Carter DC,
McArdle CS. An evaluation of the prognostic factors in gastric cancer : the effects of chemotherapy on survival. Br J
Surg 1987;74:715–21.
Preusser P, Achterrath W, Wilke H, Lenaz L, Fink U, Heinicke
A, et al. Chemotherapy of gastric cancer. Cancer Treat Rev
1988;15:257–77.
Wilke H, Preusser P, Fink U, Achterrath W, Meyer H-J, Stahl
M, et al. New development in the treatment of gastric carcinoma. Semin Oncol 1990;17(1 Suppl. 2):61–70.
W: Cancer
TS Expression and 5-FU Resistance in Gastric Carcinoma/Yeh et al.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
Yeh KH, Cheng AL, Chen YC, Chen BR, Lee WJ, Lin JT, et al.
Five-drug combination chemotherapy (FAPEL) for advanced
gastric cancer: a pilot study. J Formos Med Assoc 1994;93:20–
4.
Cheng AL, Yeh KH, Chen YC, Lin JT, Chen BR, Liu MY, et
al. PE-HDFL: an effective combination chemotherapy for
advanced gastric cancers [abstract 1582]. Proc Am Soc Clin
Oncol 1996;15:495.
Hsu CH, Yeh KH, Chen LT, Liu JM, Jan CM, Lin JT, et al.
Weekly 24-hour infusion of high-dose 5-fluorouracil and
leucovorin in the treatment of advanced gastric cancers: an
effective and low-toxic regimen for patients with poor general condition. Oncology 1997;54:275–80.
Preusser P, Wilke H, Achterrath W, Fink U, Lenaz L, Heinicke
A, et al. Phase II study with combination of etoposide, doxorubicin, and cisplatin in advanced measurable gastric cancer. J Clin Oncol 1989;7:1310–7.
Rougier PH, Ducreux M, Mahjoubi M, Pignon JP, Bellefqih
S, Oliverira J, et al. Efficacy of combined 5-fluorouracil and
cisplatinum in advanced gastric carcinomas: a phase II trial
with prognostic factor analysis. Eur J Cancer 1994;30A:1263–
9.
Kelson D, Atiq OT, Saltz L, Niedzwiecki D, Ginn D, Chapman
D, et al. FAMTX versus etoposide, doxorubicin, and cisplatin: a random assignment trial in gastric cancer. J Clin
Oncol 1992;10:541–8.
Robey-Cafferty SS, Ajani JA, Ota DM, Roth JA, Bruner JM.
Histologic observations and p-glycoprotein expression in
gastric and esophageal adenocarcinomas treated with preoperative chemotherapy. Arch Pathol Lab Med 1991;
115:807–12.
Wallner J, Depisch D, Gsur A, Gotzl M, Haider K, Pirker R.
MDR1 gene expression and its clinical relevance in primary
gastric carcinomas. Cancer 1993;71:667–71.
Peters GJ, van der Wilt CL, van Groeningen CJ, Smid K,
Meijer S, Pinedo HM. Thymidylate synthase inhibition after
administration of fluorouracil with or without leucovorin
in colon cancer patients: implications for treatment with
fluorouracil. J Clin Oncol 1994;12:2035–42.
Tsujinaka T, Kido Y, Shiozaki H, Iijima S, Homma T, Sakaue
M. Schedule-dependent inhibition of thymidylate synthase
by 5-fluorouracil in gastric cancer. Cancer 1992;70:2761–5.
Johnston PG, Liang CM, Henry S, Chabner BA, Allegra CJ.
Production and characterization of monoclonal antibodies
that localize human thymidylate synthase in the cytoplasm
of human cells and tissue. Cancer Res 1991;51:6668–76.
Johnston PG, Drake JC, Trepel J, Allegra CJ. Immunological
quantitation of thymidylate synthase using monoclonal antibody TS106 in 5-fluorouracil–sensitive and –resistant human cancer cell lines. Cancer Res 1992;52:4306–12.
Hsu SM, Raine L, Fanger H. Use of avidin-biotin-peroxidase
complex (ABC) in immunoperoxidase techniques: a compar-
/ 7bc2$$1089
04-10-98 14:21:22
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
canxa
1631
ison between ABC and unlabelled antibody (PAP) procedures. J Histochem Cytochem 1981;29:577–80.
Johnston PG, Fisher ER, Rockette HE, Fisher B, Wolmark N,
Drake JC, et al. The role of thymidylate synthase expression
in prognosis and outcome of adjuvant chemotherapy in patients with rectal cancer. J Clin Oncol 1994;12:2640–7.
Kaplan EL, Meier P. Nonparametric estimation from incomplete observation. J Am Stat Assoc 1958;53:457–81.
Peto R, Pike MC, Armitage P, Breslow NE, Cox DR, Howard
SV, et al. Design and analysis of randomized clinical trials
requiring prolonged observation of each patient (Part II). Br
J Cancer 1977;35:1–39.
Estimating and comparing means. In: Dawson-Saunders B,
Trapp RG. Basic and clinical biostatistics. London: Appleton & Lange, Inc., 1994:99–124.
MacDonald JS, Schein PS, Woolley PV, Smythe T, Ueno W,
Hoth D, et al. 5-Fluorouracil, doxorubicin, and mitomycin
(FAM) combination chemotherapy for advanced gastric cancer. Ann Intern Med 1980;93:533–6.
Wils J. The treatment of advanced gastric cancer. Semin Oncol 1996;23:397–406.
Machover D, Goldschmidt E, Chollet P, Metzger G, Zittoun
J, Marquet J, et al. Treatment of advanced colorectal and
gastric adenocarcinomas with 5-fluorouracil and high-dose
folinic acid. J Clin Oncol 1986;4:685–96.
Berenberg JL, Tangen C, Macdonald JS, Hutchins LF, Natale
RB, Oishi N, et al. Phase II study of 5-fluorouracil and folinic
acid in the treatment of patients with advanced gastric cancer:
a Southwest Oncology Group study. Cancer 1995;76:715–9.
Johnston PG, Lenz HJ, Leichman CG, Danenberg KD, Allegra
CJ, Danenberg PV, et al. Thymidylate synthase gene and
protein expression correlate and are associated with response to 5-fluorouracil in human colorectal and gastric
tumors. Cancer Res 1995;55:1407–12.
Lenz HJ, Leichman CG, Danenberg KD, Danenberg PV, Groshen
S, Cohen H, et al. Thymidylate synthase mRNA level in adenocarcinoma of the stomach: a predictor for primary tumor response and overall survival. J Clin Oncol 1996;14:176–82.
Barbour KW, Berger SH, Berger FG. Single amino acid substitution defines a naturally occuring genetic variant of human
thymidylate synthase. Mol Pharmacol 1990;37:515–8.
Chaudhary PM, Roninson IB. Induction of multidrug resistance in human cells by transient exposure to different chemotherapeutic drugs. J Natl Cancer Inst 1993;85:632–9.
Westwick JK, Bielawska AE, Dbaibo G, Hannun VA, Brenner
DA. Ceramide activates the stress-activated protein kinases.
J Biol Chem 1995;270:22689–92.
Jarvis WD, Grant S, Kolesnick RN. Ceramide and induction
of apoptosis. Clin Cancer Res 1996;2:1–6.
Wang CY, Mayo MW, Baldwin AS. TNF- and cancer therapyinduced apoptosis: potentiation by inhibition of NF-erkB.
Science 1996;274:784–7.
W: Cancer
Документ
Категория
Без категории
Просмотров
5
Размер файла
350 Кб
Теги
847
1/--страниц
Пожаловаться на содержимое документа