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

A 60-year-old female patient with gastric cancer and lymph node and liver metastases was treated with a combination of tegafur and uracil (UFT) (375 mg/m2/day) and mitomycin C (MMC) (5 mg/m2 once weekly). On day 15, when diarrhea appeared, chemotherapy was stopped immediately. On day 21, the WBC decreased to 900/microl and high fever developed. Despite treatment with granulocyte colony-stimulating factor and antibiotics, leukopenia persisted and the patient went into septic shock on day 26. On day 34, WBC increased to 5,400/microl and she recovered, with reduction in the size of the lymph node and liver metastases. Pharmacokinetic examination after intravenous injection of low-dose MMC (0.5 mg/m2) showed a markedly high peak plasma concentration (PPC), a large area under the time-versus-concentration curve (AUC) and reduced clearance. Similarly, oral administration of UFT (tegafur 300 mg/body) produced a relatively higher PPC and a larger AUC of 5-fluorouracil (FU). The activity of dihydropyrimidine dehydrogenase, the rate-limiting enzyme in the metabolism of FU, in peripheral mononuclear cells was within the normal range (0.265 nmol/min/mg). MMC is believed to have played a large part in inducing the severe toxicity observed in this patient. Physicians should be aware of the possibility of severe toxicity during treatment with UFT and MMC, although details of its incidence and mechanism are unclear.
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PMID:A case of advanced gastric cancer complicated by severe toxicity induced by a combination of tegafur, uracil and mitomycin C, and associated with abnormal pharmacokinetics. 889 81

We analyzed the pyrimidine metabolite in the urine of a patient with severe mucositis and hand and foot syndrome, who was administered 5-fluorouracil for recurrence of gastric cancer. From our analysis, it was suggested that the patient had decreased dihydropyrimidine dehydrogenase activity. Dihydropyrimidine dehydrogenase activity is usually measured in peripheral blood mononuclear cells, but this time it was estimated from the analysis of uracil, dihydrouracil, thymine, and dihydrothymine in the urine. We concluded that urinary analysis of the pyrimidine metabolism is effective as screening for the prediction and prevention of 5-fluorouracil toxicity.
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PMID:[A case of gastric cancer with decreased dihydropyrimidine dehydrogenase activity]. 967 86

The cycle-specific schedule-dependent antimetabolite 5-fluorouracil (5-FU) has been in clinical use for 40 years and has evolved as an important agent in the treatment of a large spectrum of tumors, including all gastrointestinal cancers, breast cancer, head and neck cancer, and bladder cancer. Over these 4 decades, there has been an increased understanding of the optimal method and schedule of administration of 5-FU. Furthermore, the concept of pharmacomodulation and biochemical modulation of 5-FU to increase therapeutic efficacy has emerged as a new strategy in cancer chemotherapy. The specific mechanism by which 5-FU induces lethal injury may vary depending on the administration schedule or the type of biochemical modulation applied. The optimal infusion duration and dose intensity of 5-FU continues to be debated as does the question of the need for biochemical modulation when using infusional schedules. Infusional administration of 5-FU has become the gold standard in the treatment of head and neck cancer, esophageal cancer, gastric cancer (in Great Britain), and rectal and anal cancer. The recent availability of oral formulations for 5-FU in conjunction with the capability of manipulating the metabolism of 5-FU, particularly with dihydropyrimidine dehydrogenase (DPD) inhibitors, may provide a substantial incremental improvement in these therapies by eliminating the need for parenteral administration and the use of ambulatory infusion pumps.
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PMID:Infusional 5-FU: historical evolution, rationale, and clinical experience. 983 Jun 20

S-1 is a novel oral anticancer drug, composed of tegafur (FT), gimestat (CDHP) and otastat potassium (Oxo) in a molar ratio of 1:0.4:1, based on the biochemical modulation of 5-fluorouracil (5-FU). CDHP inhibits dihydropyrimidine dehydrogenase (DPD), an enzyme which degrades 5-FU, and maintains prolonged 5-FU concentrations in the blood and tumours. Oxo is distributed in the gastrointestinal tract at a high concentration after oral administration and alleviates gastrointestinal toxicity due to 5-FU. S-1 improves the tumour-selective toxicity of 5-FU by the actions of two modulators, CDHP and Oxo. We conducted a late phase II clinical trial of S-1 as an open trial in patients with advanced gastric cancer, to confirm its antitumour effect and adverse reactions. 51 patients with advanced gastric cancer were enrolled in the trial. S-1 was administered orally twice daily after meals, at a standard dose of 80 mg/m2/day. One course consisted of consecutive administration for 28 days and 14 days' rest. Administration was repeated over four courses. A complete response was obtained in 1 patient and partial responses in 24 patients, producing a response rate of 49% (25/51) (95% confidence interval (CI) 35.9-62.3%). The incidence of adverse reactions was 78% (40/51) and that of adverse reactions of grades 3 and 4 was 20%. Adverse reactions of grades 3 and 4 included a decrease in the haematocrit, leucopenia, granulocytopenia, diarrhoea, malaise and proteinuria. No serious unexpected adverse reactions were observed. In conclusion, S-1 was effective and well tolerated in patients with advanced gastric cancer.
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PMID:Late phase II study of novel oral fluoropyrimidine anticancer drug S-1 (1 M tegafur-0.4 M gimestat-1 M otastat potassium) in advanced gastric cancer patients. 989 58

S-1 is a novel oral fluorouracil antitumor drug that combines three pharmacological agents: tegafur (FT), which is a prodrug of 5-fluorouracil (5-FU); 5-chloro-2,4-dihydroxypyridine (CDHP), which inhibits dihydropyrimidine dehydrogenase (DPD) activity; and potassium oxonate (Oxo), which reduces gastrointestinal toxicity. Phase I and early Phase II clinical trials have already been completed. On the basis of the results of these trials, 80 mg/m2/day, given daily in two divided doses after breakfast and supper, a 28-day consecutive oral regimen is recommended. In this study, we investigated the pharmacokinetics of 5-FU, intact FT, CDHP, and Oxo, after administration of S-1, at a standard dose of 80 mg/m2/day, in advanced cancer patients. Twelve patients were recruited to the study; 5 patients with gastric cancer, 4 with colorectal cancer, and 3 with breast cancer. Among them, analysis was conducted on 12 patients for single administration and on 10 patients for consecutive administration. The initial dose of S-1 for each patient was determined according to his/her body surface area (BSA) as follows: for BSA < 1.25 m2, 80 mg/body/day; for 1.25 m2 < or = BSA < 1.5 m2, 100 mg/day; and for 1.5 m2 < or = BSA, 120 mg/day. For single administration, half of the standard dose was used. For 28-day consecutive administration, the standard dose was given daily in two divided doses. The average single dose per BSA was 35.9 mg/m2 (31.7-39.7 mg/m2). Pharmacokinetic parameters of plasma 5-FU were as follows: Cmax, 128.5 +/- 41.5 ng/ml; Tmax, 3.5 +/- 1.7 h; AUC(0-14), 723.9 +/- 272.7 ng x h/ml; and T(1/2), 1.9 +/- 0.4 h. In the 28-day consecutive regimen, there were no fluctuations in pharmacokinetics nor any drug accumulation. Because the pharmacokinetics of orally administered S-1 is almost similar to that of continuous i.v. infusion of 5-FU, we concluded that S-1 may improve patients' quality of life.
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PMID:Pharmacokinetic study of S-1, a novel oral fluorouracil antitumor drug. 1047 78

The measurement of thymidylate synthetase (TS) and dihydropyrimidine dehydrogenase (DPD) enzymatic activities and mRNA levels in tumors may be useful in predicting tumor sensitivity to 5-fluorouracil (5-FU). Forty-one patients with advanced gastric cancer gave informed consent and were enrolled in this study. Biopsy specimens of gastric cancer were obtained preoperatively through gastrofiberscopy and used to determine TS and DPD mRNA levels. We also measured TS and DPD enzymatic activities and mRNA levels in surgically resected gastric cancer samples, as well as in adjacent normal gastric mucosa. TS and DPD activities were measured using the TS-binding assay and a radioenzymatic assay, respectively, while mRNA levels were measured by semi-quantitative reverse transcription-PCR (RT-PCR) co-amplified with glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as an internal standard. In resected tumor specimens, TS and DPD activities ranged from 7.1 to 176.6 fmol/mg protein and from 3.6 to 99.8 pmol/min/mg protein, respectively, while TS and DPD mRNA levels ranged from 0.50 to 21.12 and from 0.014 to 7:22, respectively. There were no significant correlations between TS/DPD levels and other clinicopathological factors, except for low DPD mRNA levels in undifferentiated carcinoma. Both TS activity and mRNA levels were significantly higher in tumor tissues compared to normal adjacent mucosa. In contrast, there was no significant difference between tumoral and non-tumoral DPD activity, although tumor tissue showed significantly lower DPD mRNA levels than non-tumoral tissue. High tumoral TS mRNA levels in preoperative biopsy specimens from patients with stage III/IV was associated with poor survival outcome after surgery compared with patients with low tumoral TS mRNA levels. In contrast, DPD levels had no influence on prognosis. We conclude that high tumoral TS levels and low tumoral DPD mRNA may indicate the selective cytotoxicity of 5-FU on gastric cancer, and that tumoral TS mRNA levels may be a prognostic factor for patients with stage III/IV gastric cancer.
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PMID:Thymidylate synthetase and dihydropyrimidine dehydrogenase levels in gastric cancer. 1069 32

A new class of 5-halogenated pyrimidine analogs substituted at the 6-position was evaluated as competitive inhibitors of thymidine phosphorylase (TPase). The most potent member of the series was 5-chloro-6-(2-iminopyrrolidin-1-yl)methyl-2,4(1H,3H)-pyrimidine dio ne hydrochloride (TPI), which has an apparent K(i) value of 1.7 x 10(-8) M. TPI selectively inhibited the activity of TPase, but not that of uridine phosphorylase, thymidine kinase, orotate phosphoribosyltransferase, or dihydropyrimidine dehydrogenase. In vitro inhibition studies of TPI using a thymidine analogue, 5-trifluoromethyl-2'-deoxyuridine (F(3)dThd), as the substrate demonstrated that F(3)dThd phosphorolytic activity was inhibited markedly by TPI (1 x 10(-6) M) in extracts from the liver, small intestine, and tumors of humans, from the liver and small intestine of cynomolgus monkeys, and from the liver of rodents, but not from the liver or small intestine of dogs or the small intestine of rodents, suggesting that the distribution of TPase differs between humans and animal species, and that TPI could contribute to the modulation of TPase in humans. When F(3)dThd or 5-iodo-2'-deoxyuridine (IdUrd) was coadministered to mice with TPI at a molar ratio of 1:1, the blood levels of F(3)dThd (or IdUrd) were about 2-fold higher than when F(3)dThd (or IdUrd) was administered alone. In monkeys, the maximum concentration (C(max)) and the area under the concentration-time curve (AUC) after oral F(3)dThd alone were 0.23 microg/mL and 0.28 microg. hr/mL, respectively, but markedly increased to 15.18 microg/mL (approximately 70-fold) and 28.47 microg. hr/mL (approximately 100-fold), respectively, when combined with equimolar TPI. Combined oral administration of TPI significantly potentiated the antitumor activity of F(3)dThd on AZ-521 human stomach cancer xenografts in nude mice. In conclusion, TPI may contribute not only to inhibition of TPase-mediated biological functions but also to potentiation of the biological activity of various 2'-deoxyuridine and thymidine derivatives by combining with them.
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PMID:Structure and activity of specific inhibitors of thymidine phosphorylase to potentiate the function of antitumor 2'-deoxyribonucleosides. 1073 23

We investigated the correlation between tumor sensitivity to 5-fluorouracil (5-FU) and enzymatic activities of thymidylate synthetase (TS) and dihydropyrimidine dehydrogenase (DPD) in human gastric cancer specimens. Forty-one patients with advanced gastric cancer gave informed consent and were enrolled in the study. Biopsy specimens of gastric cancer were obtained preoperatively through gastrofiberscopy and used to determine TS and DPD messenger RNA (mRNA) levels. TS and DPD enzyme activity and mRNA levels were also measured in resected tumor tissue samples obtained after surgical resection. TS and DPD activity were measured using the TS-binding assay and a radioenzymatic assay, respectively, while mRNA levels were measured by semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR), with co-amplification of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as an internal standard. 5-FU sensitivity of resected tumor specimens was measured by the tetrazolium-based colorimetric assay (MTT assay). Both TS and DPD mRNA levels correlated well between biopsied and resected tumor specimens. A statistically significant correlation was also observed between mRNA levels in biopsied specimens and enzymatic activities in resected specimens. DPD levels significantly correlated with 5-FU sensitivity, such that high DPD activity and high DPD mRNA levels resulted in low sensitivity to 5-FU. In contrast, no correlation was observed between TS activity or TS mRNA levels and 5-FU sensitivity. We conclude that tumor DPD mRNA level, as assessed from biopsy specimens obtained by gastrofiberscopy, may be a useful indicator in predicting tumor sensitivity to 5-FU in patients with gastric cancer.
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PMID:Dihydropyrimidine dehydrogenase and messenger RNA levels in gastric cancer: possible predictor for sensitivity to 5-fluorouracil. 1074 51

Many reports have demonstrated that thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) are biomarkers for the response and prognosis of patients treated with 5-fluorouracil (5-FU)-based chemotherapy. A newly developed orally administered drug, fluoropyrimidine (S-1), has been developed with clinical efficacy when combined with an inhibitor of DPD. In this study, the relationship between immunoreactivity to TS and DPD in biopsy specimens and the effects of chemotherapy was investigated in 41 patients treated with S-1 therapy for advanced gastric cancer. Response rates were 54% (13/24) in TS(+) and 53% (9/17) in TS(-) patients (p=0.938), and those of DPD(+) and (-) patients were 61% (11/18) and 48% (11/23) (p=0.397), respectively. The median survival time of all the subjects was 253 days. There was no significant difference in median survival time between TS(+) patients (284 days) and (-) patients (189 days: p=0.670). The 18 DPD(+) patients had median survival times slightly longer (338 days) than the 23 patients with DPD(-) (207 days: p=0.206). This study indicates that S-1 may be effective in the treatment of gastric cancer patients, regardless of intratumoral TS and DPD immunoreactivity status. Further studies are needed to confirm these results with larger numbers of patients.
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PMID:Clinical implications of immunoreactivity of thymidylate synthase and dihydropyrimidine dehydrogenase in gastric cancer treated with oral fluoropyrimidine (S-1). Study Group of S-1 for Gastric Cancer. 1099 74

Because of the low chemosensitivity of gastric cancer to conventionally available agents, several approaches were investigated to design "order made" treatments using chemosensitivity tests, including the histoculture drug response assay (HDRA) which was useful in evaluating the appropriate cancer chemotherapy for the patients with Stage III/IV gastric cancer. A recent investigation using a molecular biological method was introduced to predict the sensitivity of gastric cancer specimens to 5-fluorouracil (5-FU) by dihydropyrimidine dehydrogenase (DPD) activity and its mRNA. The low activity of DPD and DPD mRNA resulted in the low sensitivity to 5-FU, although thymidylate synthetase activity was not related to the sensitivity to 5-FU. This method is promising, since a small amount of material obtained through gastrofiberscopy will be adequate to assess DPD mRNA to predict the sensitivity to 5-FU. On the other hand, some randomized control trials with a huge cohort have indicated the usefulness of a "docetaxel + cisplatin + 5-FU" regimen for advanced and recurrent gastric cancer, and "5-FU + LV + radiation" as an adjuvant therapy for advanced gastric cancer. Furthermore, the efficacy of adjuvant chemotherapy after curative resection for gastric cancer was warranted by a meta-analysis of 19 published randomized trials. The "order made" and "standard" therapies will be complementary in the further development of chemotherapy against gastric cancer.
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PMID:[Recent advance in gastric cancer chemotherapy]. 1110 35


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