Dihydropyrimidine dehydrogenase expression in preoperative biopsy and surgically resected specimens of gastric carcinoma

Nozawa, Hiroaki; Tsukui, Hajime; Nishida, Kouji; Yakumaru, Kazuhiro; Nagawa, Hirokazu; Sekikawa, Takayoshi

doi:10.1007/s00280-002-0422-x

Cited by 12 publications

(14 citation statements)

References 8 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Reactivity of gastric cancers with the monoclonal antibody was significantly lower than that with the polyclonal antibody (15 of 18 gastric cancers were nonreactive with the monoclonal antibody). In contrast, Nozawa et al reported a high rate (96%) of DPD immunoreactivity in the biopsied and surgical specimens of gastric cancers by using the polyclonal antibody [23].…”

Section: Discussionmentioning

confidence: 99%

“…Significant correlation between the immunohistochemical DPD expression and the 5-FU resistance or poor prognosis has been demonstrated in pulmonary, mammary, and oral carcinomas [9,10,15,22]. Nozawa et al reported that DPD expression in gastric carcinoma was comparable between the biopsy samples and resected surgical specimens [23]. Takenoue et al described that DPD immunoreactivity in colorectal cancer tissues and cell lines was correlated with the protein levels [29].…”

Section: Introductionmentioning

confidence: 97%

“…Immunohistochemical analysis of DPD has been performed in a limited number of studies [9,10,15,22,23,29]. Significant correlation between the immunohistochemical DPD expression and the 5-FU resistance or poor prognosis has been demonstrated in pulmonary, mammary, and oral carcinomas [9,10,15,22].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Immunohistochemical Demonstration of Dihydropyrimidine Dehydrogenase in Normal and Cancerous Tissues

Kamoshida

Shiogama

Matsuoka

et al. 2003

Acta Histochem. Cytochem.

View full text Add to dashboard Cite

Dihydropyrimidine dehydrogenase (DPD) is a rate-limiting enzyme in the catabolism of 5-fluorouracil (5-FU). Previous studies have suggested that high enzyme activities and mRNA levels of DPD are involved in the resistance of cancers to 5-FU. For immunohistochemically demonstrating the tumor resistance to 5-FU, we determined the most suitable and reproducible condition of antigen retrieval for DPD localization in formalin-fixed, paraffin-embedded sections, and analyzed DPD expression in various types of normal and cancerous tissues. Pressure cooking in ethylenediaminetetraacetic acid, pH 8.0, was the best choice for retrieving the antigenicity of DPD. In normal tissues, DPD immunoreactivity was consistently detected in squamous epithelia, hepatocytes, Clara cells, ductal/glandular epithelia of various organs, myoepithelial cells, and non-epithelial cells such as macrophages, plasma cells, and part of the endothelial cells and fibroblasts. DPD was strongly expressed in adenocarcinomas of the lung, gallbladder and pancreas, hepatocellular carcinomas, and transitional cell carcinomas of the urinary bladder. Squamous cell carcinomas of the pharynx and lung were moderately reactive. Carcinomas of the breast and stomach revealed less consistent and less intense reactivity. Colorectal adenocarcinomas were not immunoreactive. The polyclonal antibody gave a broader and stronger reactivity than the monoclonal antibody KM1915, particularly in the normal epidermis and skin appendage as well as in squamous cell carcinomas and gastric cancers. The present results hopefully contribute to further investigations, in which the immunohistochemical demonstration of DPD is utilized as a tool of tailor-made chemotherapy for selecting of patients with cancer resistant to 5-FU and its derivatives.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

See 1 more Smart Citation

Immunohistochemical Demonstration of Dihydropyrimidine Dehydrogenase in Normal and Cancerous Tissues

Kamoshida

Shiogama

Matsuoka

et al. 2003

Acta Histochem. Cytochem.

View full text Add to dashboard Cite

show abstract

“…Intratumoural DPD expression inversely correlates with the sensitivity to 5-FU (Ishikawa et al, 1999;Nozawa et al, 2002) in gastric cancer. However, our data indicated that the antitumour effect of S-1 for gastric cancer was not influenced by intratumour DPD gene expression, regardless of the combination of CPT-11.…”

Section: Discussionmentioning

confidence: 99%

Thymidylate synthase predictive power is overcome by irinotecan combination therapy with S-1 for gastric cancer

et al. 2004

View full text Add to dashboard Cite

The predictive values of thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) gene expressions were retrospectively evaluated in patients with gastric cancer treated by a regimen containing S-1. The study population consisted of 53 patients registered into different two phase II studies for metastatic gastric cancer; 27 patients treated by S-1-alone study: 26 patients treated with S-1 combined with irinotecan (CPT-11). TS and DPD gene expressions in primary tumours were measured by the realtime reverse transcription PCR method. There was no statistical difference in DPD gene expression in terms of response in cases treated with S-1 alone and those treated with S-1 plus CPT-11. TS mRNA of responding tumours was lower than that of nonresponding ones when treated with S-1 (Po0.005). In the S-1-alone group, taking TS cutoff as the median values, the response rate in the low TS group was 50%, but only 8% in the high TS group (Po0.05). Patients with low TS gene expression survived longer than those with high TS gene expression (Po0.0001). However, there was no statistically significant difference in response rate and survival between patients with low TS tumours and those with high TS tumours, when the cutoff was taken as the median value of TS gene expression in the group treated with S-1 plus CPT-11. In conclusion, treatment effects of S-1 monotherapy for gastric cancer were determined by the status of TS gene expression, regardless of DPD gene expression. TS predictive power was overcome by CPT-11 combination therapy with S-1. The main mode of action of 5-fluorouracil (5-FU) is thought to be through its active metabolite, 5-fluoro-deoxyuridine-monophosphate (FdUMP), which suppresses thymidylate synthase (TS), an essential DNA synthetic enzyme that catalyses the methylation of deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP) (Langenbach et al, 1972;Peters et al, 1995). 5-FU is catabolised to 2-fluoro-b-alanine by dihydropyrimidine dehydrogenase (DPD), the first and rate-limiting enzyme (Heggie et al, 1987).S-1 is a new oral fluorinated pyrimidine, in which tegafur (FT) has been combined with two 5-FU modulating substances: 5-chloro-2,4-dihydroxypyrimidine (gimeracil, CDHP), and potassium oxonate (oteracil potassium, Oxo), in a molar ratio of FT: CDHP: Oxo ¼ 1 : 0.4 : 1 (Shirasaka et al, 1996). FT is a prodrug of 5-fluorouracil (FU), which is absorbed after oral ingestion followed by conversion to 5-FU. CDHP reversibly inhibits the activity of DPD , resulting in the increase of antitumour activity (Tatsumi et al, 1987). Two phase II studies of S-1 showed activity in gastric cancer, accompanied by mild-to-moderate toxicity. The response rate was 44 -49% and the median survival time was 207 -250 days, with 1-and 2-year survival rates of 36 -37 and 14%, respectively (Sakata et al, 1998;Koizumi et al, 2000).Irinotecan hydrochloride (CPT-11) is a water-soluble, semisynthetic derivative of camptothecin (CPT) that retains the original antitumour effects of CPT-11 due to the inhibition ...

show abstract

“…A possible explanation for the higher potency of TXT and S-1 is that antitumor effects of S-1 in gastric cancer have been shown not to be influenced by intratumor DPD gene expression, although intratumor DPD expression inversely correlates with the sensitivity to 5-FU. 29,39,53 Overall, however, predicting the efficacy of S-1 in a clinical setting might be of major interest in the future including assessments of the status of OPRT, DPD and TS. Finally, our data strongly indicate that the combination chemotherapy of TXT and S-1 is effective against gastric carcinomas and is therefore a good candidate as a standard chemotherapeutic strategy in treating these tumors.…”

Section: Discussionmentioning

confidence: 99%

Synergistic effects of docetaxel and S‐1 by modulating the expression of metabolic enzymes of 5‐fluorouracil in human gastric cancer cell lines

Wada

Yoshida

Suzuki

et al. 2006

Intl Journal of Cancer

View full text Add to dashboard Cite

We have recently demonstrated in a Phase I/II study that combination chemotherapy with docetaxel (TXT) and S-1 is active against metastatic gastric carcinomas. To elucidate the mechanisms underlying the synergistic effects of these drugs, both the growth inhibitory effects and the expression profiles of enzymes involved in fluorouracil (5-FU) metabolism were examined in vitro and in vivo. TXT alone and in combination with 5-FU inhibited the growth of each of the 5 gastric cancer cell lines that we examined , in a time-and dosedependent manner. Moreover, striking synergistic effects were observed in TMK-1 cells in vitro with IC 50 values of between 4.73 and 0.61 nM 5-FU. Furthermore, in TMK-1 xenografts, 5-FU/ TXT cotreatments exhibited synergistic antitumor effects. The combination of S-1 and TXT, however, exhibited greater growthinhibitory effects than the 5-FU/TXT cotreatments. The mechanisms underlying these synergistic effects of S-1 and TXT were examined by expression and activity analyses of the 5-FU metabolic enzymes. The expression of thymidylate synthase (TS), and dihydropyrimidine dehydrogenase (DPD) were decreased 50 and 73% of control levels, respectively, and that of orotate phosphorybosyl transferase (OPRT) was increased by 3.9-fold at the protein level. These findings suggested that biochemical modulation of the 2 drugs had occurred, which was further confirmed by the results of the activity assays. These data strongly indicate that a combination chemotherapy of TXT and S-1 is effective against gastric carcinomas and is therefore a good candidate as a standard chemotherapeutic strategy in treating these tumors. ' 2006 Wiley-Liss, Inc.Key words: gastric cancer; TMK-1; docetaxel; 5-fluorouracil; S-1; TS, thymidylate synthase; DPD, dihydropyrimidine dehydrogenase; OPRT, orotate phosphorybosyl transferase; combination effectIn spite of recent advances in the development of both diagnostic and therapeutic tools, gastric cancer is still a major cause of death throughout the world. Moreover, because many patients are still diagnosed at only the late stages of this disease, recurrent tumors are often detected even after curative surgery. In such patients, chemotherapy is one of the main treatment strategies that is employed, as it has been shown to improve prognoses. 1-3 However, a standard regimen of the treatment of metastatic gastric cancer has not been yet established in Japan.5-Fluorouracil (5-FU) is widely used an anticancer agent and is currently considered to be a key drug in clinical chemotherapeutic treatments for gastrointestinal cancers, such as esophageal, 4 gastric 5 and colorectal. 6 In addition, 5-FU has been also used to treat both breast 7 and cervical 8 cancers. 5-FU is catabolized to 2-fluorob-alanin by the first and rate-limiting enzyme of its metabolic pathway, dihydropyrimidine dehydrogenase (DPD). The functional effects of 5-FU are thought to occur through its active metabolite, 5-fluorodeoxyuridine diphosphate (FdUMP) 9,10 which, together with the coenzyme 5,10-methylenethtrahydr...

show abstract

Dihydropyrimidine dehydrogenase expression in preoperative biopsy and surgically resected specimens of gastric carcinoma

Abstract: It is considered that immunohistochemical analysis of DPD expression in gastric carcinoma using biopsied tissue is a technically feasible method to assess the expression of DPD in the tumor prior to surgical resection.

Cited by 12 publications

References 8 publications

Immunohistochemical Demonstration of Dihydropyrimidine Dehydrogenase in Normal and Cancerous Tissues

Immunohistochemical Demonstration of Dihydropyrimidine Dehydrogenase in Normal and Cancerous Tissues

Thymidylate synthase predictive power is overcome by irinotecan combination therapy with S-1 for gastric cancer

Synergistic effects of docetaxel and S‐1 by modulating the expression of metabolic enzymes of 5‐fluorouracil in human gastric cancer cell lines

Contact Info

Product

Resources

About