Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024623 (gastric cancer)
 36,219 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thymidylate synthase (TS) is the target enzyme of 5-fluorouracil (5-FU), and dihydropyrimidine dehydrogenase (DPD) is the key enzyme in the 5-FU catabolic pathway. We wanted to determine whether the TS and DPD mRNA expression levels of gastric and colorectal cancer patients would be affected by tegafur (futrafur:FT)-based chemotherapy and whether changes in their expression might be responsible for patient outcome. Thirty-five patients with resectable advanced primary gastric cancer and 36 patients with resectable advanced primary colorectal cancer were the subjects of this study. They all underwent neoadjuvant chemotherapy with protracted infusion of FT alone or FT plus low doses of cisplatin. The TS and DPD mRNA expression levels of endoscopic biopsy specimens before chemotherapy and surgical specimens after chemotherapy were measured by TaqMan reverse transcription-PCR assay using glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as the internal standard. There was a significant difference in the DPD mRNA levels during chemotherapy in the colorectal cancers. Although the TS and DPD levels were unrelated to any conventional histopathological grade factors, colorectal cancer patients whose surgical specimens contained lower TS and DPD mRNA levels had longer disease-free intervals. The results of this study suggest that FT may affect DPD mRNA expression in colorectal cancer patients, that TS/DPD expression can be regarded as an independent prognostic factor, and that colorectal cancer patients with low TS and low DPD mRNA are candidates for FT-based adjuvant chemotherapy. In addition, quantitative analysis of the change in TS/DPD mRNA in surgical specimens during FT-based chemotherapy might be a more accurate means of predicting the post-operative disease-free interval of colorectal cancer patients than analysis of endoscopic specimens before chemotherapy. There also seems to be a relation between regulation of TS and DPD during FT chemotherapy. Elucidation of the mechanisms regulating TS and DPD mRNA expression might make it possible to predict sensitivity and/or toxicity to FT.
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PMID:Changes in intratumoral thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) mRNA expression in colorectal and gastric cancer during continuous tegafur infusion. 1144 49

The patient was a 65-year-old woman with type 3 gastric cancer (por) in the upper third of the stomach invading esophagus. Because of No. 16 lymph node swelling on abdominal CT examination, she was treated with FLP (5-fluorouracil + Leucovorin + cisplatin) as a neoadjuvant chemotherapy (NAC). The activities of thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) in the primary tumors upon endoscopic examination were 2.72 pmol/g tissue and 129.1 pmol/mg/min, respectively. After the second course, we carried out lower esophagectomy and spleno-total gastrectomy with D3 including the No. 16 lymph nodes. Histopathological examination of resected specimens showed dense fibrosis and xanthogranulomatous inflammation with foamy cells and giant cells. No residual carcinoma was seen (complete response). The patient is still alive with no sign of recurrence 1 year after surgery. NAC by combination of FLP is thought to be effective for the treatment of highly advanced gastric cancer, especially in cases with locally advanced disease and lymph node metastasis such as the present. Although no relations were seen between NAC effects and TS, DPD activities and TSIR in primary tumors in 12 gastric cancer patients, the survival rate of a low DPD activity group was significantly better than a high group in 106 cases undergoing adjuvant chemotherapy including 5-FU after surgery.
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PMID:[A complete response after neoadjuvant chemotherapy for advanced gastric cancer with esophageal invasion]. 1181 67

The rate-limiting enzyme to catabolize 5-fluorouracil (5-FU) is dihydropyrimidine dehydrogenase (DPD), which expression in cancerous tissue is reported to have a relation with anti-tumor effect for 5-FU. In this study, we evaluated the immunohistochemical expression in gastric cancer using two different kinds of anti-human DPD antibody, KM1915 and KM1919. However, recognition of both antibody was mimetic in human gastric cancer, and strong expression of DPD was observed in the interstitial tissue when using KM1919. There is a positive relationship between immunohistochemical expression by KM1915 and mRNA expression in human gastric cancer. Immunohistochemical study with KM1915 might be a clinically useful method to evaluate the expression of DPD in paraffin-embedded materials.
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PMID:[Dihydropyrimidine dehydrogenase expression in gastric cancer using anti-human dihydropyrimidine dehydrogenase monoclonal antibody]. 1186 31

TS-1, a DPD inhibitory fluoropyrimidine, is a novel oral formation of 5-fluorouracil (5-FU). In patients with advanced gastric cancer, the response rate was reportedly over 40%. We report three cases of advanced gastric cancer treated using TS-1 in combination with a low-dose of cisplatinum (CDDP) that well responded. Case 1: A 62-year-old women underwent total gastrectomy. Ten weeks later, she suffered intestinal obstruction due to peritoneal recurrence of gastric cancer. Eighty mg of TS-1 in combination with bi-weekly administration of CDDP (10 mg) improved her intestinal obstruction. Case 2: A 50-year-old man suffered peritoneal recurrence of gastric cancer. Computed tomography (CT) showed intestinal obstruction, ascites, and hydronephrosis. After 100 mg of TS-1 in combination with bi-weekly administration of CDDP (20 mg) for 1 year, CT showed almost complete improvement of peritonitis carcinomatosa. Case 3: A 58-year-old man, who suffered advanced gastric cancer with peritonitis carcinomatosa, was administrated 100 mg of TS-1 in combination with bi-weekly administration of CDDP (20 mg). After 2 months of administration, remarkable improvement was observed in the upper gastrointestinal series. Adverse reactions, which were grade 1 for stomatitis, were observed only in case 1. All three patients are alive (case 1 and 2 have survived more than one year) and therapy is continuing. In conclusion, combined chemotherapy of TS-1 and low-dose CDDP was effective and well tolerable for advanced gastric cancer patients. It was suggested that effective biochemical modulation might be achieved by these two drugs.
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PMID:[Three cases of advanced gastric cancer treated by TS-1 in combination with low-dose cisplatinum]. 1186 38

In a clinical study, a newly developed anticancer drug, TS-1 capsule, which contained tegafur (FT) and 5-chloro-2,4-dihydroxypyridine, an inhibitor of dihydropyrimidine dehydrogenase, was orally administered to five gastric cancer patients (patients 1-5). The total area under the plasma FT concentration-time curve in patient 1 was four-fold higher than in other patients. Since cytochrome P450 2A6 (CYP2A6) has been reported to metabolize FT to yield 5-fluorouracil (5-FU), it was postulated that the poor metabolic phenotype of patient 1 was caused by mutations of the CYP2A6 gene. Thus, alleles for the CYP2A6 genes derived from patient 1 were completely sequenced. It was found that one allele was CYP2A6*4C, which was a whole deleted allele for the human CYP2A6 gene. The other allele was a novel mutant allele (CYP2A6*11) in which thymine at nucleotide 670 was changed to cytosine. The nucleotide change caused an amino acid change from serine at residue 224 to proline. To examine whether or not the amino acid change affected CYP2A6 activity, we expressed an intact or mutant CYP2A6 together with NADPH-P450 oxidoreductase in Escherichia coli, and compared the capacity of the wild and mutant enzymes to metabolize FT to 5-FU. The Vmax value for FT metabolism by the mutant CYP2A6 was approximately one-half of the value of the intact CYP2A6, although the Km values were nearly the same. From these results, we conclude that the poor metabolic phenotype of patient 1 was caused by the existence of the two mutant alleles, CYP2A6*4C and the new variant CYP2A6*11.
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PMID:A novel mutant allele of the CYP2A6 gene (CYP2A6*11 ) found in a cancer patient who showed poor metabolic phenotype towards tegafur. 1204 67

This study was designed to investigate the role of thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD) on tumour progression and sensitivity to 5'-deoxy-5-fluorouridine (5'-DFUR). Tumour tissue was obtained from surgically resected samples from 93 patients with primary gastric cancer. Tumour TP and DPD expression levels were determined by the enzyme-linked immunosorbent assay (ELISA) system and compared with several clinicopathological factors and in vitro sensitivity to 5'-DFUR. DPD showed no correlation with any clinicopathological factors. However, the TP level was significantly correlated with the depth of tumour, lymphatic invasion and venous invasion. In comparison with 5'-DFUR sensitivity, there was a weak inverse correlation between the DPD level and the sensitivity to 5'-DFUR (r(s)=-0.361). Furthermore, the TP/DPD ratio showed a significant correlation with 5'-DFUR sensitivity (r(s)=0.634). In a subgroup of patients with postoperative 5'-DFUR administration, the survival rate was significantly better in patients with a high TP/DPD ratio (n=8) than in those with low TP/DPD ratio (n=14) (P=0.0140). These results suggest that sensitivity to 5'-DFUR is predictable by measurement of both TP and DPD levels.
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PMID:Role of thymidine phosphorylase and dihydropyrimidine dehydrogenase in tumour progression and sensitivity to doxifluridine in gastric cancer patients. 1246 Jul 81

We used real-time reverse-transcription polymerase chain reaction (RT-PCR) to assay expression of the mRNA of thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) in gastric cancer tissue with the objective of establishing a system to measure TS and DPD in ultra-low-volume samples. Nude mouse xenografts of 5 human gastric cancer cell lines and 85 clinical samples were used as the specimens in this study. Sensitivity to 5-fluorouracil (5-FU) was determined on the basis of the relative tumor proliferation rate in mice and the results of ATP assay using serum-free cultures of the clinical samples. mRNA expression was measured in tumor tissue by real-time RT-PCR using the ABI PRISM 7700 system. The values for expression of the mRNA for TS and DPD were corrected according to the level of glyceraldehyde-3-phosphate dehydrogenase mRNA expression. The xenografts yielded correlations between TS and DPD mRNA expression and the activity of the enzymes (TS: rs=0.700, DPD: rs=0.900), and an inverse correlation was noted between the mRNA levels and sensitivity to 5-FU (TS: rs=-0.900, DPD: rs=-0.800). The clinical samples showed an inverse correlation between 5-FU sensitivity and mRNA expression (TS: rs=-0.518, DPD: rs=-0.564). Sensitivity to 5-FU was noted only in cases in which TS mRNA expression and DPD mRNA expression were both low. Real-time RT-PCR can provide a highly sensitive assessment of TS and DPD mRNA expression in gastric cancer, and it was useful for predicting 5-FU sensitivity.
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PMID:Quantitative measurement of thymidylate synthase and dihydropyrimidine dehydrogenase mRNA level in gastric cancer by real-time RT-PCR. 1249 74

Survival of patients with advanced gastric cancer with Krukenberg's tumor is poor. We report the case of a good response in a 37-year-old woman who had type 4 gastric cancer, diagnosed after the operation of Krukenberg's tumor, and then was treated with TS-1, a DPD inhibitory fluoropyrimidine, in combination with a low-dose cisplatinum (CDDP). Endoscopic gastric biopsy showed signet-ring cell adenocarcinoma and moderately differentiated tubular adenocarcinoma, and computed tomography (CT) showed the para-aortic lymph node metastasis before the chemotherapy. The patient was treated with two courses of TS-1 (100 mg/day, day 1-21) plus CDDP (10 mg/m2, day 1-5, 8-12, 15-19) with two-week interval. After the first course, gastric biopsy did not show any cancer cells and lymph node metastasis had disappeared. Serum CA19-9 decreased gradually week by week during the chemotherapy, even during the washout period after the first course, and was normalized after two courses. This case suggests that the combination of TS-1 and low-dose CDDP is effective against type 4 advanced gastric cancer.
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PMID:[A case of type 4 gastric cancer, diagnosed after operation for Krukenberg's tumor, treated by TS-1 plus low-dose cisplatinum]. 1261 Aug 79

A 68-year-old male with a history of gastric resection for gastric cancer underwent resection of the sigmoid colon for a sigmoid colon cancer in February, 2000. The cancer was classified as stage III b. After operation, l-LV + 5-FU therapy was administered, but metastases to the abdominal wall, right inguinal lymph node and spleen developed in succession, and resection was repeated. In October 2001, 1 year and 8 months after sigmoidectomy, however, multiple metastasis to the intraperitoneal lymph node had developed. As surgery was not indicated, TS-1/CDDP combined chemotherapy was started. TS-1 80 mg/day was administered for 4 weeks, the drug was withdrawn for 2 weeks and CDDP 80 mg was injected by intravenous drip at the 8th day of TS-1 administration, which was used as one course. From the second course after inception of the administration, CA19-9 decreased, and after the third course the upper intraperitoneal metastatic lesion disappeared on CT. CR has been continued for 4 months up to the present. Our results suggest a possibility that this therapy is effective not only for gastric cancer but also for colon cancer. This therapy can be administered at home. It is considered to be a useful therapy from the viewpoint of QOL as well. The high DPD activity of the tumor may have been one reason this treatment was effective. This case also seems significant from the viewpoint of attaining individualization of the drug selection in chemotherapy.
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PMID:[A case report--TS-1/CDDP combined chemotherapy found effective for metastatic recurrence after operation for colon cancer]. 1261 Aug 80

The current basic and clinical studies of S-1 (TS-1) were reviewed. S-1 is a novel oral dihydropyrimidine dehydrogenase (DPD) inhibitory fluoropyrimidine (DIF) based on a biochemical modulation of 5-fluorouracil (5-FU); S-1 contains tegafur (FF) and two types of enzyme inhibitor, 5-chloro-2,4-dihydroxypyridine (CDHP) and potassium oxonate (Oxo) in a molar ratio of 1:0.4:1. In pharmacokinetic studies, S-1 showed high 5-FU concentration in blood for long periods of time. In a combined analysis of two pivotal late phase II studies in gastric cancer, the overall response rate was 44.6% (45/101), and median survival time and 1-year survival rate were 244 days and 37%, respectively. A postmarketing survey was conducted, and in the interim analysis, tolerability and safety profiles were shown in 3294 patients with gastric cancer. The oral dose form and low incidence of adverse reactions permit treatment on an outpatient basis. To evaluate the survival benefit of S-1 in advanced gastric cancer, a phase III study of S-1 vs 5-FU vs cisplatin (CDDP) plus irinotecan (CPT-11) has been conducted. The effect of S-1 in adjuvant chemotherapy is also promising. Currently, a phase III study of surgery alone vs S-1 in patients with curative resection of gastric cancer is in progress. Further therapeutic benefits are expected to be gained by combining S-1 with other chemotherapeutic agents. Several preliminary results of combination phase I/II studies of S-1 with CDDP or CPT-11 have recently been obtained, and phase II studies are in progress. Thus, S-1 is currently the first candidate as the standard anticancer drug for gastric cancer. Further evaluations by well-controlled clinical trials are still needed.
Gastric Cancer 2003
PMID:S-1 in gastric cancer: a comprehensive review. 1277 12


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