Response to fluorouracil therapy in cancer patients: the role of tumoral dihydropyrimidine dehydrogenase activity.

Etienne, Marie‐Christine; Chéradame, S; Fischel, Jean‐Louis; Formento, Patricia; Dassonville, O.; Renée, Nicole; Schneider, M.; Thyss, Antoine; Démard, F; Milano, Gérard

doi:10.1200/jco.1995.13.7.1663

Cited by 252 publications

(173 citation statements)

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“…Moreover, the enhanced activity of DPD by 5-FU has been shown in a number of previous studies to confer tumor resistance to 5-FU, both in vitro and in clinical studies. [32][33][34][35] Low levels of DPD mRNA expression has also been associated with a low sensitivity to 5-FU and has also been correlated with a low sensitivity to fluoropyrimidine-based chemotherapy in colorectal cancer patients. [36][37][38][39] TS as well as DPD is an enzyme that plays key roles in 5-FU resistance in carcinoma cells.…”

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

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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...

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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

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“…An overview of clinical relevant studies is presented in Table 2. Most studies have been performed in colorectal cancer, 68,[88][89][90][91] some in gastric, [92][93][94] head and neck, [95][96][97] and non-small-cell lung cancer, [98][99][100] and few in breast and bladder cancer. 101,102 A number of studies have indicated that there is no strong link between DPD mRNA levels and DPD protein activity levels.…”

Section: -Fluorouracilmentioning

confidence: 99%

“…An overview of relevant clinical studies is presented in Table 4. Most studies regarding TS expression in relation to chemosensitivity have been performed in patients with disseminated colorectal cancer, 68,91,[122][123][124][125][126][127][128][129][130][131][132][133][134] some in gastric cancer 94,[135][136][137][138] and few studies in head and neck cancer, 95,96,139 non-small-cell lung cancer 99,100 pancreatic and breast cancer. 84,140,141 Several factors may account for the difficult interpretation of combined clinical data.…”

Section: Impact Of Somatic Mutations and Gene Expression Levels: 5-fumentioning

confidence: 99%

Genetic factors influencing Pyrimidine-antagonist chemotherapy

et al. 2005

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Pyrimidine antagonists, for example, 5-fluorouracil (5-FU), cytarabine (ara-C) and gemcitabine (dFdC), are widely used in chemotherapy regimes for colorectal, breast, head and neck, non-small-cell lung cancer, pancreatic cancer and leukaemias. Extensive metabolism is a prerequisite for conversion of these pyrimidine prodrugs into active compounds. Interindividual variation in the activity of metabolising enzymes can affect the extent of prodrug activation and, as a result, act on the efficacy of chemotherapy treatment. Genetic factors at least partly explain interindividual variation in antitumour efficacy and toxicity of pyrimidine antagonists. In this review, proteins relevant for the efficacy and toxicity of pyrimidine antagonists will be summarised. In addition, the role of germline polymorphisms, tumourspecific somatic mutations and protein expression levels in the metabolic pathways and clinical pharmacology of these drugs are described. Germline polymorphisms of uridine monophosphate kinase (UMPK), orotate phosphoribosyl transferase (OPRT), thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD) and methylene tetrahydrofolate reductase (MTHFR) and gene expression levels of OPRT, UMPK, TS, DPD, uridine phosphorylase, uridine kinase, thymidine phosphorylase, thymidine kinase, deoxyuridine triphosphate nucleotide hydrolase are discussed in relation to 5-FU efficacy. Cytidine deaminase (CDD) and 5 0 -nucleotidase (5NT) gene polymorphisms and CDD, 5NT, deoxycytidine kinase and MRP5 gene expression levels and their potential relation to dFdC and ara-C cytotoxicity are reviewed.

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“…[9][10][11][12] On the other hand, dihydropyrimidine dehydrogenase (DPD) which is both an initial and a rate-limiting catabolic enzyme of 5-FU has been reported to play an important role in the pharmacokinetics of 5-FU and was correlated with the antitumor effectiveness of 5-FU in cancer cell lines and tumors. 9,[13][14][15][16][17][18] Recently, both basic and clinical researches have shown a correlation between the antitumor effectiveness of 5-FU and TS or DPD mRNA levels in tumors by using semiquantitative reverse-transcription polymerase chain reaction (RT-PCR). 11,12,16,[19][20][21] One of the major advantages of these methods is that they can be performed with ultralow-volume samples as compared with measurement of the enzyme activities and in vitro chemosensitivity tests.…”

mentioning

confidence: 99%

Quantitative Measurement of Thymidylate Synthase and Dihydropyrimidine Dehydrogenase mRNA Level in Gastric Cancer by Real‐time RT‐PCR

Fujiwara¹,

Terashima²,

Irinoda³

et al. 2002

Japanese Journal of Cancer Research

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1, 2) Thus, it is important to select patients in whom treatment is likely to be effective in order to improve the results of chemotherapy. In vitro anticancer drug sensitivity tests, which we developed with this goal in mind, have already yielded favorable results.3) However, tests that involve cell culturing procedures are complicated by the need for special facilities, and there can be problems with failures attributable to low cell growth.Standard regimens for gastric cancer involve some form of concomitant treatment that includes biomodulated 5-fluorouracil (5-FU) chemotherapy. 4,5) The mechanism of action of 5-FU has been explained in terms of incorporation of fluorouridine 5′-triphosphate (FUTP) into RNA, resulting in altered gene expression, or in terms of inhibition of thymidylate synthase (TS) by the active metabolite 5-fluorouridine monophosphate (FdUMP).6-8) Several reports have indicated that TS expression in the tumors was related to the sensitivity to 5-FU-based chemotherapy both in the laboratory and clinically. [9][10][11][12] On the other hand, dihydropyrimidine dehydrogenase (DPD) which is both an initial and a rate-limiting catabolic enzyme of 5-FU has been reported to play an important role in the pharmacokinetics of 5-FU and was correlated with the antitumor effectiveness of 5-FU in cancer cell lines and tumors. 9,[13][14][15][16][17][18] Recently, both basic and clinical researches have shown a correlation between the antitumor effectiveness of 5-FU and TS or DPD mRNA levels in tumors by using semiquantitative reverse-transcription polymerase chain reaction (RT-PCR). 11,12,16,[19][20][21] One of the major advantages of these methods is that they can be performed with ultralow-volume samples as compared with measurement of the enzyme activities and in vitro chemosensitivity tests.A real-time RT-PCR method based on TaqMan fluorescence methodology requires fewer steps after PCR than conventional PCR methods, simplifying the procedures 5 To whom correspondence should be addressed.

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Response to fluorouracil therapy in cancer patients: the role of tumoral dihydropyrimidine dehydrogenase activity.

Abstract: Although resistance to FU is multifactorial, the present clinical study suggests that FU catabolism in target cells is probably a determinant factor for FU responsiveness in cancer patients and justifies the clinical use of specific DPD inhibitors as FU biomodulators.

Cited by 252 publications

References 20 publications

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

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

Genetic factors influencing Pyrimidine-antagonist chemotherapy

Quantitative Measurement of Thymidylate Synthase and Dihydropyrimidine Dehydrogenase mRNA Level in Gastric Cancer by Real‐time RT‐PCR

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