Clinical Cancer Research Meeting Calendar AACR Membership
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Tsuji, T.
Right arrow Articles by Tagawa, Y.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Tsuji, T.
Right arrow Articles by Tagawa, Y.
Clinical Cancer Research Vol. 9, 3700-3704, September 1, 2003
© 2003 American Association for Cancer Research

Molecular Oncology, Markers, Clinical Correlates

Polymorphism in the Thymidylate Synthase Promoter Enhancer Region Is Not an Efficacious Marker for Tumor Sensitivity to 5-Fluorouracil-based Oral Adjuvant Chemotherapy in Colorectal Cancer

Takashi Tsuji1, Shigekazu Hidaka, Terumitsu Sawai, Tohru Nakagoe, Hiroshi Yano, Masatoshi Haseba, Hideaki Komatsu, Hisakazu Shindou, Hidetoshi Fukuoka, Megumi Yoshinaga, Shinichi Shibasaki, Atsushi Nanashima, Hiroyuki Yamaguchi, Tohru Yasutake and Yutaka Tagawa

Division of Surgical Oncology, Department of Translational Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences [T. T., S. H., T. S., T. N., H. Yan., M. H., H. K., H. S., H. F., M. Y., S. S., A. N., H. Yam., T. Y.], and Nagasaki University School of Health Sciences [Y. T.], Nagasaki 852-8501, Japan


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Thymidylate synthase (TS) is the target enzyme of 5-fluoropyrimidines. The TS gene promoter enhancer region (TSER) possesses tandem, repeated, regulatory sequences that are polymorphic in humans. This polymorphism has been reported to influence TS expression in vitro and in vivo. In this study, we assessed whether or not the TSER genotype is an efficacious marker for tumor sensitivity to 5-fluorouracil (5-FU)-based oral adjuvant chemotherapy for colorectal cancer. One hundred and thirty-five Japanese patients who received curative resection and 5-FU-based oral adjuvant chemotherapy were studied. TSER genotypes of the tumors were analyzed by PCR. The numbers of repeated sequences of representative bands were determined by direct sequence. The genotypes of two-/two-repeats (TSER 2/2), two-/three-repeats (TSER 2/3), three-/three-repeats (TSER 3/3), and three-/five-repeats (TSER 3/5) were found in 11 (8.1%), 32 (23.7%), 85 (63.0%), and 7 (5.2%) tumors, respectively. Patients were classified into two groups: TSER 2/2 or 2/3 group; and the TSER 3/3 group. The relationship between the TSER genotype group and disease-free intervals was analyzed by univariate and multivariate analyses. Five-year disease-free survivals of the TSER 2/2 or 2/3 group and the TSER 3/3 group were 77% and 75%, respectively (P = 0.89). Multivariate analysis revealed that stage was the only independent prognostic factor and that the TSER genotype did not have a prognostic significance (hazard ratio for TSER 3/3, 0.91; P = 0.84). In conclusion, TSER genotype is not an efficacious marker for tumor sensitivity to 5-FU-based oral adjuvant chemotherapy for Japanese colorectal cancer patients after curative resection.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
5-FU,2 a classical TS inhibitor, plays a central role in chemotherapy for colorectal cancer. Previous studies have shown that sensitivity to 5-FU-based chemotherapy is associated with the intratumoral level of TS (1 , 2) . The TS gene is localized on chromosome 18 p11.32 and has a polymorphic, tandem, repeated sequence in its promoter enhancer region (TSER). In a transient expression assay of cancer cells, TS genes with the three-repeat sequence were reported to have greater expression activity than those with the two-repeat sequence (3) . In clinical specimens of gastrointestinal cancer, TS gene expression is significantly higher in tumors with the three-/three-repeat sequence (TSER 3/3) than in those with the two-/two-repeat sequence (TSER 2/2) and two/three-repeat sequence (TSER 2/3) (4) . These studies suggest the possibility that TSER polymorphism may be a novel predictor of the efficacy of TS-directed chemotherapy (5) . However, to our knowledge, there have not been any investigations that have estimated the significance of the TSER polymorphism in adjuvant TS-directed chemotherapy for colorectal cancers. The aim of this study was to assess whether or not TSER polymorphism can predict the efficacy of 5-FU-based oral adjuvant chemotherapy in patients with colorectal cancer who underwent curative surgery.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patients.
We studied 135 patients with stage I-III colorectal cancer who underwent "curability A resection" and received postoperative adjuvant chemotherapy from February 1994 to December 1998 at the Division of Surgical Oncology, Department of Translational Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences. The study did not consist of patients with either synchronous or metachronous multiple colorectal cancers. The American Joint Committee on Cancer classification and stage grouping was used to classify tumors (6) . Curability A resection was postoperatively defined according to the Japanese Classification of Colorectal Carcinoma (7) . Each tumor was histopathologically classified in accordance with the WHO criteria presented by Jass and Sobin (8) . The 135 patients included 16 patients with stage I cancer, 61 patients with stage II cancer, and 58 patients with stage III cancer. Thirty-two tumors were classified as well-differentiated adenocarcinomas, 98 tumors were classified as moderately differentiated adenocarcinomas, 3 tumors were classified as poorly differentiated adenocarcinomas, 1 tumor was classified as a mucinous carcinoma, and 1 tumor was classified as a signet ring cell carcinoma. None of the patients was given preoperative chemotherapy or radiotherapy. All patients received oral adjuvant chemotherapy that started 3 weeks after curative surgery and lasted for 12 months [83 patients received Carmofur, 300 mg, 3x/day; 52 patients received UFT (a mixture composed of a fixed 1:4 molar ratio of tegafur and uracil), 400 mg, 2x/day]. The mean age of patients was 62 years (range, 29–78 years). Sixty-nine of the patients were male, and 66 were female. Eighty-one tumors were localized to the colon, and 54 tumors were in the rectum. All patients underwent standard follow-up examinations, including laboratory testing every 3 months. Chest roentgenograms, computed tomography, and abdominal ultrasonography were performed every 6 months. Colonoscopies were performed annually. The median follow-up period was 48 months (minimum follow-up, 4.2 months). Written informed consent was obtained from all patients.

PCR and Direct Sequencing for TSER Polymorphism.
Genomic DNA was extracted from tumor tissues stored at -80°C using a standard protocol. PCR was performed using TSER-specific primers. Primer sequences and reaction conditions were as reported previously (4) . After amplification, the PCR product was electrophoresed on a 2.8% NuSieve agarose gel (Biocompare, Inc., Burlingame, CA) containing ethidium bromide. The number of repeats in representative bands was determined by direct sequencing (9) . We determined the genotype as TSER 2/2 or 3/3 (homozygous) when only one band was observed. When two bands were observed, the genotype was decided as TSER 2/3 or 3/5 (heterozygous) without consideration for differences in band intensities.

Statistical Analysis.
Statistical analyses were performed using the computer program STATISTICA (StatSoft, Tulsa, OK). Two variables with continuous data, age and maximum tumor diameter, were classified into two groups, based on the median of each variable (66 years and 4.5 cm, respectively). Categorical data were analyzed by {chi}2 or Fisher’s exact test. Analysis of survival was performed using the Kaplan-Meier method, and differences between survival curves were tested for significance using the log-rank test. Multivariate analysis was performed with Cox’s proportional hazard regression model to assess the effects of different variables on patient survival. All tests were two-tailed, and P < 0.05 was considered to be statistically significant.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Frequency of the TSER Polymorphism.
The frequencies of TSER genotypes were as follows: TSER 2/2, 11 tumors (8.1%); TSER 2/3, 32 tumors (23.7%); TSER 3/3, 85 tumors (63.0%); and TSER 3/5, 7 tumors (5.2%). Fig. 1Citation shows representative examples of the TSER genotypes in colorectal cancers. Among the 32 tumors with TSER 2/3, 7 tumors (21.9%) showed an obvious difference in intensity between two bands. These tumors were thought to have LOH at the TSER polymorphic locus, but we judged the genotype as TSER 2/3.



View larger version (69K):
[in this window]
[in a new window]
[Download PPT slide]
  		Fig. 1. TSER genotypes in colorectal cancer. Lane M, DNA size marker, {phi}174/HaeIII digest; Lane 1, TSER genotype 2/2; Lane 2, TSER 2/3; Lane 3, TSER 2/3 with LOH; Lane 4, TSER 3/3; Lane 5, TSER 3/5. Numbers on the left indicate DNA fragment size (bp).

 
Survival Analysis and TSER Polymorphism.
We excluded patients with TSER 3/5 from the survival analysis because a significant difference in TS expression has been reported between tumors with TSER 2/2 and 2/3 and tumors with TSER 3/3 (4) . Patients were classified into two groups: the TSER 2/2 and 2/3 group; and the TSER 3/3 group. There was not a significant correlation between clinicopathological features and the TSER genotype groups (Table 1)Citation . Fig. 2Citation shows the disease-free survival of patients with colorectal cancer, according to TSER genotype groups. Five-year disease-free survivals of the TSER 2/2 and 2/3 group and the TSER 3/3 group were 77% and 75%, respectively (P = 0.89, log-rank test). In multivariate Cox’s regression analysis, stage was the only independent prognostic factor, and the hazard ratio for the TSER 3/3 group was 0.91 (95% CI, 0.37–2.27; Table 2Citation ).


View this table:
[in this window]
[in a new window]

  		Table 1 Comparison of clinicopathological characteristics between the TSER 2/2 or 2/3 group and the TSER 3/3 group in 128 colorectal cancer patients who received curative resection and adjuvant chemotherapy

 


View larger version (17K):
[in this window]
[in a new window]
[Download PPT slide]
  		Fig. 2. Comparison of survival between the TSER 2/2/or 2/3 group and the TSER 3/3 group in 128 patients with colorectal cancer who received curative resection and adjuvant chemotherapy. P was calculated by log-rank test.

 

View this table:
[in this window]
[in a new window]

  		Table 2 Prognostic variables for survival in Cox regression analysis

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Based on prospective studies (10 , 11) , Japanese clinical oncologists often administer oral 5-FU-based adjuvant chemotherapy to colorectal cancer patients after curative resection. Patients prefer oral chemotherapy to i.v. chemotherapy (12) . In the interim report of the National Surgical Adjuvant Breast and Bowel Project C-06, there were no differences in toxicity grade and spectrum between i.v. and oral adjuvant chemotherapies for stage II-III colorectal cancer (13) . Therefore, it is important to research an efficacious marker of tumor sensitivity to 5-FU-based oral adjuvant chemotherapy for colorectal cancers.

In preoperative chemoradiation therapy for rectal cancer and chemotherapy for metastatic colorectal cancer, the possibility of TSER genotype as a response marker to 5-FU-based chemotherapy has been reported. Villafranca et al. (14) analyzed the TSER genotype in pretreatment biopsy specimens from 65 rectal cancer patients who received preoperative radiation and 5-FU-based chemotherapy. They reported that the probability of downstaging by preoperative chemoradiation therapy is significantly higher in tumors with TSER 2/2 and 2/3 than in those with TSER 3/3. Marsh et al. (15) reported that median survival time was longer in patients with the TSER 2/2 or 2/3 genotypes when compared with those with the TSER 3/3 genotype. The study was performed in 24 patients with metastatic colorectal cancer who were treated with a bolus injection of 5-FU (15) . In this study, we estimated the potential of using the TSER genotype as an efficacious marker of tumor sensitivity to 5-FU-based oral adjuvant chemotherapy for colorectal cancer. However, it was not found to be an efficacious marker for oral adjuvant chemotherapy.

Kawakami et al. (16) analyzed TSER genotypes by PCR, TS mRNA expression with real-time PCR, and TS enzymatic activity by 5-fluoro-dUMP binding assay in 130 colorectal carcinomas. They did not find a relationship between TS genotype and mRNA expression level, but tumors with TSER 2/2 and 2/3 had significantly lower TS enzymatic activity than tumors with TSER 3/3 (16) . Thus, the classification into two groups (TSER 2/2 and 2/3 group and TSER 3/3group) in this study is consistent with previous studies in the literature.

LOH on 18p11 is a problem in TSER genotyping using tumor tissue (17) . DNA extracted from frozen tumor materials was contaminated with DNA from normal stromal cells in this study. We judged the genotype as heterozygous (e.g., TSER 2/3) and disregarded allelic imbalances when two bands were observed. Thus the TSER genotypes in this study are thought to agree with those of patients’ normal tissue. The frequency of LOH on 18p in colorectal cancer is reported to be 40% (18) . In this study, 22% of tumors with TSER 2/3 were suspected to have LOH on 18p11. It is not known whether TS expression levels change in tumor cells with or without LOH on 18p11.

Care must be taken to recognize that ethnic variation exists in the TSER genotype. In the Caucasian and Southwest Asian populations, the frequencies of TSER 2/2, 2/3, and 3/3 are reported to be 16–19%, 43–44%, and 38–40%, respectively (19) . In this study, the frequencies of TSER 2/2, 2/3, and 3/3 were 8%, 24%, and 63%, respectively. Therefore, the allele frequency of three repeats tends to be higher in Japanese than in the Caucasian and Southwest Asian population. In general, 5-year disease-free survival rates in colorectal cancer patients who received curative surgery and 5-FU-based adjuvant chemotherapy ranged from 71% to 77% (20) . In this study, the overall 5-year disease-free survival of the TSER 2/2 and 2/3 group and TSER 3/3 group was 75.5%. However, the frequency of allele three repeats was observed to be higher when compared with other ethnic populations. This similarity of the overall 5-year disease-free survival supports the lack of a prognostic significance for the TSER genotype. However, the clinical significance of the TSER genotype must be estimated independently in other populations because of ethnic variation in the allele frequencies.

Previous studies have described that low TS expression in metastatic colorectal cancers is a predictor of clinical response to 5-FU-based therapy (1 , 2) . On the other hand, in curatively resected colorectal cancers, tumors with low TS expression have no survival benefit with 5-FU-based adjuvant chemotherapy (21) . Recently, Edler et al. (22) analyzed TS expression by immunohistochemical staining in 862 patients with Dukes’ stage B and C colorectal cancer and found that high TS expression is an independent prognostic factor. However, patients with tumors with low TS expression had an impaired outcome after 5-FU-based adjuvant chemotherapy (22) . Accordingly, it remains controversial whether or not TS expression is an efficacious marker of tumor sensitivity to 5-FU-based adjuvant chemotherapy for colorectal cancer.

In conclusion, TSER genotype is not a significant efficacious marker in oral adjuvant chemotherapy for Japanese colorectal cancer patients. Future studies combining several factors, such as TS, thymidine phosphorylase, and dihydropyrimidine dehydrogenase, must be planned to find a beneficial marker in adjuvant chemotherapy for colorectal cancer.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 To whom requests for reprints should be addressed, at Division of Surgical Oncology, Department of Translational Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, Sakamoto 1-7-1, Nagasaki 852-8501, Japan. Phone: 81-95-849-7304; Fax: 81-95-849-7306; E-mail: bannv{at}bolero.plala.or.jp Back

2 The abbreviations used are: 5-FU, 5-fluorouracil; TS, thymidylate synthase; TSER, thymidylate synthase promoter enhancer region; LOH, loss of heterozygosity; CI, confidence interval. Back

Received 10/21/02; revised 3/24/03; accepted 4/ 5/03.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Johnston P. G., Lenz H. J., Leichman C. G., Danenberg K. D., Allegra C. J., Danenberg P. V., Leichman L. Thymidylate synthase gene and protein expression correlate and are associated with response to 5-fluorouracil in human colorectal and gastric tumors. Cancer Res., 55: 1407-1412, 1995.[Abstract/Free Full Text]
  2. Aschele C., Debernardis D., Casazza S., Antonelli G., Tunesi G., Blado C., Lionetto R., Maley F., Sobrero A. Immunohistochemical quantitation of thymidylate synthase expression in colorectal cancer metastases predicts for clinical outcome to fluorouracil-based chemotherapy. J. Clin. Oncol., 17: 1760-1770, 1999.[Abstract/Free Full Text]
  3. Horie N., Aiba H., Oguro K., Hojo H., Takeishi K. Functional analysis and DNA polymorphism of the tandemly repeated sequence in the 5'-terminal regulatory region of the human gene for thymidylate synthase. Cell Struct. Funct., 20: 191-197, 1995.[Medline]
  4. Kawakami K., Omura K., Kanehira E., Watanabe Y. Polymorphic tandem repeats in the thymidylate synthase gene is associated with its protein expression in human gastrointestinal cancers. Anticancer Res., 19: 3249-3252, 1999.[Medline]
  5. Relling T., Dervieux T. Pharmacogenetics and cancer therapy. Nat. Rev. Cancer, 1: 99-108, 2001.[CrossRef][Medline]
  6. Fleming I. D., Cooper J. S., Henson D. E., Hunter R. V. P., Kennedy B. J., Murphy G. P., O’Sullivan B., Sobin L. H., Yarbro J. W. Colon and rectum Fleming I. D. Cooper J. S. Henson D. E. Hunter R. V. P. Kennedy B. J. Murphy G. P. O’Sullivan B. Sobin L. H. Yarbro J. W. eds. . AJCC Cancer Staging Manual, 5th ed. 83-90, Lippincott-Raven New York 1997.
  7. Japanese Society for Cancer of the Colon and Rectum . Japanese Classification of Colorectal Carcinoma, first English edition Kanehara Tokyo 1997.
  8. Jass J. R., Sobin L. H. Definition and explanatory notes. Large intestine Jass J. R. Sobin L. H. eds. . Histopathological Typing of Intestinal Tumors, 29-40, Springer-Verlag New York 1989.
  9. Tsuji T. Relationship between DNA heterogeneity and genetic alterations in colorectal carcinomas. Cytometry Research, 7: 25-33, 1997.
  10. Sakamoto J., Hamada C., Kodaira S., Nakazato H., Ohashi Y. Adjuvant therapy with oral fluoropyrimidines as main chemotherapeutic agents after curative resection for colorectal cancer: individual patient data meta-analysis of randomized trials. Jpn. J. Clin. Oncol., 29: 78-86, 1999.[Abstract/Free Full Text]
  11. Kato T., Ohashi Y., Nakazato H., Koike A., Saji S., Suzuki H., Takagi H., Nimura Y., Hasumi A., Baba S., Manabe T., Maruta M., Miura K., Yamaguchi A. Efficacy of oral UFT as adjuvant chemotherapy to curative resection of colorectal cancer: multicenter prospective randomized trial. Langenbeck’s Arch. Surg., 386: 575-581, 2002.[CrossRef][Medline]
  12. Borner M. M., Schöffski P., de Wit R., Caponigro F., Comella G., Sulkes A., Greim G., Peters G. J., van der Born K., Wanders J., de Boer R. F., Martin C., Fumoleau P. Patient preference and pharmacokinetics of oral modulated UFT versus intravenous fluorouracil and leucovorin: a randomized crossover trial in advanced colorectal cancer. Eur. J. Cancer, 38: 349-358, 2002.
  13. Smith R. E., Lembersky B. C., Wieand H. S., Colangelo L., Mamounas E. P. UFT/leucovorin vs 5-FU/leucovorin in colon cancer. Oncology (Basel), 14 (Suppl. 9): 24-27, 2000.
  14. Villafranca E., Okruzhnov Y., Dominguez M. A., Garcia-Foncillas J., Azinovic I., Martinez E., Illarramendi J. J., Arias F., Monge R. M., Salgado E., Angeletti S., Brugarolas A. Polymorphisms of the repeated sequences in the enhancer region of the thymidylate synthase gene promoter may predict downstaging after preoperative chemoradiation in rectal cancer. J. Clin. Oncol., 19: 1779-1786, 2001.[Abstract/Free Full Text]
  15. Marsh S., McKay J. A., Cassidy J., McLeod H. L. Polymorphism in the thymidylate synthase promoter enhancer region in colorectal cancer. Int. J. Oncol., 19: 383-386, 2001.[Medline]
  16. Kawakami K., Salonga D., Park J. M., Danenberg K. D., Uetake H., Brabender J., Omura K., Watanabe G., Danenberg P. V. Different lengths of a polymorphic repeat sequence in the thymidylate synthase gene affect translational efficiency but not its gene expression. Clin. Cancer Res., 7: 4096-4101, 2001.[Abstract/Free Full Text]
  17. Zinzindohouse F., Ferraz J-M., Laurent-Puig P. Thymidylate synthase promoter polymorphism. J. Clin. Oncol., 19: 3442 2001.[Free Full Text]
  18. Vogelstein B., Fearon E. R., Kern S. E., Hamilton S. R., Preisinger A. C., Nakamura Y., White R. Allelotype of colorectal carcinomas. Science (Wash. DC), 244: 207-211, 1989.[Abstract/Free Full Text]
  19. Marsh S., Collie-Duguid E. S. R., Li T., Liu X., McLeod H. L. Ethnic variation in the thymidylate synthase enhancer region polymorphism among Caucasian and Asian populations. Genomics, 58: 310-312, 1999.[CrossRef][Medline]
  20. Zaniboni A. Adjuvant chemotherapy in colorectal cancer with high-dose leucovorin and fluorouracil: Impact on disease-free survival and overall survival. J. Clin. Oncol., 15: 2432-2441, 1997.[Abstract/Free Full Text]
  21. Takenoue T., Nagawa H., Matsuda K., Fujii S., Nita M. E., Hatano K., Kitayama J., Tsuruo T., Muto T. Relation between thymidylate synthase expression and survival in colon carcinoma, and determination of appropriate application of 5-fluorouracil by immunohistochemical method. Ann. Surg. Oncol., 7: 193-198, 2000.[Abstract]
  22. Edler D., Glimelius B., Hallström M., Jakobsen A., Johnston P. G., Magnusson I., Ragnhammar P., Blomgren H. Thymidylate synthase expression in colorectal cancer: a prognostic and predictive marker of benefit from adjuvant fluorouracil-based chemotherapy. J. Clin. Oncol., 20: 1721-1728, 2002.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 JCOHome page
E. Dotor, M. Cuatrecases, M. Martinez-Iniesta, M. Navarro, F. Vilardell, E. Guino, L. Pareja, A. Figueras, D. G. Mollevi, T. Serrano, et al.
Tumor Thymidylate Synthase 1494del6 Genotype As a Prognostic Factor in Colorectal Cancer Patients Receiving Fluorouracil-Based Adjuvant Treatment
J. Clin. Oncol., April 1, 2006; 24(10): 1603 - 1611.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
V. Garcia, J. M. Garcia, C. Pena, J. Silva, G. Dominguez, A. Hurtado, I. Alonso, R. Rodriguez, M. Provencio, and F. Bonilla
Thymidylate synthase messenger RNA expression in plasma from patients with colon cancer: prognostic potential.
Clin. Cancer Res., April 1, 2006; 12(7): 2095 - 2100.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
A. Jakobsen, J. N. Nielsen, N. Gyldenkerne, and J. Lindeberg
Thymidylate Synthase and Methylenetetrahydrofolate Reductase Gene Polymorphism in Normal Tissue As Predictors of Fluorouracil Sensitivity
J. Clin. Oncol., March 1, 2005; 23(7): 1365 - 1369.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
S. Popat, R. Hubner, and R.S. Houlston
Systematic Review of Microsatellite Instability and Colorectal Cancer Prognosis
J. Clin. Oncol., January 20, 2005; 23(3): 609 - 618.
[Abstract] [Full Text] [PDF]

Home page
 CarcinogenesisHome page
J. Zhang, Y. Cui, G. Kuang, Y. Li, N. Wang, R. Wang, W. Guo, D. Wen, L. Wei, F. Yu, et al.
Association of the thymidylate synthase polymorphisms with esophageal squamous cell carcinoma and gastric cardiac adenocarcinoma
Carcinogenesis, December 1, 2004; 25(12): 2479 - 2485.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Tsuji, T.
Right arrow Articles by Tagawa, Y.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Tsuji, T.
Right arrow Articles by Tagawa, Y.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online