A phase II study of combined chemotherapy with methotrexate, 5-fluorouracil, and low-dose cisplatin (MFP) for histologically diffuse-type advanced and recurrent gastric cancer (KDOG9501)

Nakayama, Norisuke; Koizumi, Wasaburo; Tanabe, Satoshi; Sasaki, Takeshi; Saigenji, Katsunori

doi:10.1007/s10120-006-0371-x

Cited by 7 publications

(3 citation statements)

References 28 publications

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“…Together these factors modulate the dNTP pools and are additionally the targets for specific agents that have medical applications (e.g. 5-Fluorouracil and methotrexate) (28,54,55). While it is well appreciated that activation of the RB pathway can repress the expression of these genes (27,56), our studies demonstrate that deficiency in SWI/SNF activity precludes the ability to effectively modulate their gene expression.…”

Section: Discussionmentioning

confidence: 61%

SWI/SNF Activity Is Required for the Repression of Deoxyribonucleotide Triphosphate Metabolic Enzymes via the Recruitment of mSin3B

Gunawardena

Fox

Siddiqui

et al. 2007

Journal of Biological Chemistry

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The SWI/SNF chromatin remodeling complex plays a critical role in the coordination of gene expression with physiological stimuli. The synthetic enzymes ribonucleotide reductase, dihydrofolate reductase, and thymidylate synthase are coordinately regulated to ensure appropriate deoxyribonucleotide triphosphate levels. Particularly, these enzymes are actively repressed as cells exit the cell cycle through the action of E2F transcription factors and the retinoblastoma tumor suppressor/p107/p130 family of pocket proteins. This process is found to be highly dependent on SWI/SNF activity as cells deficient in BRG-1 and Brm subunits fail to repress these genes with activation of pocket proteins, and this deficit in repression can be complemented, via the ectopic expression of BRG-1. The failure to repress transcription does not involve a blockade in the association of E2F or pocket proteins p107 and p130 with promoter elements. Rather, the deficit in repression is due to a failure to mediate histone deacetylation of ribonucleotide reductase, dihydrofolate reductase, and thymidylate synthase promoters in the absence of SWI/SNF activity. The basis for this is found to be a failure to recruit mSin3B and histone deacetylase proteins to promoters. Thus, the coordinate repression of deoxyribonucleotide triphosphate metabolic enzymes is dependent on the action of SWI/SNF in facilitating the assembly of repressor complexes at the promoter.SWI/SNF is a multisubunit complex that regulates transcription through its ability to remodel chromatin (1-4). This complex contains either BRG-1 or Brm as the central ATPase. Additionally, the complex is composed of accessory proteins termed BRG-1-associated factors (5). Together, these subunits form a 2-MDa complex that utilizes the energy from ATP hydrolysis to catalyze changes in chromatin structure. Given this central role for SWI/SNF in transcriptional control, the complex is associated with multiple biological processes including differentiation, hormonal signaling, and cell cycle control. The SWI/SNF complex is important for modulating transcriptional programs related to cell cycle control, and aberrations in SWI/SNF subunits are progressively associated with tumorigenesis (6, 7).Specifically, SNF5 is a tumor suppressor involved in rhabdoid tumors (8 -10), while sporadic loss of multiple other subunits is observed in a litany of tumor types (11). In general, the loss of these factors has been implicated in deregulation of target genes associated with cell cycle control, particularly those regulated by the RB/E2F signaling axis (12-14).The retinoblastoma tumor suppressor (RB) 2 was identified based on loss in the pediatric eye tumor of the same name (15-18). Subsequently, the gene product has been extensively analyzed and demonstrated to function as a transcriptional modulator. Specifically, RB and related pocket proteins p107/p130 bind to members of the E2F family of transcription factors and mediate transcriptional repression (19 -23). These effects on transcription are mediated by th...

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Section: Discussionmentioning

confidence: 61%

SWI/SNF Activity Is Required for the Repression of Deoxyribonucleotide Triphosphate Metabolic Enzymes via the Recruitment of mSin3B

Gunawardena

Fox

Siddiqui

et al. 2007

Journal of Biological Chemistry

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“…Diffuse-type gastric carcinoma, according to the Lauren classification, is highly metastatic and characterized clinically by rapid disease progression and poor prognosis. Studies have shown that diffuse-type gastric cancer patients were more sensitive to S-1 chemotherapy than intestinal-type ones [38][39][40][41]. However, there are no reports demonstrating the correlation of Lauren classification with 5-FU metabolic enzymes.…”

Section: Discussionmentioning

confidence: 99%

OPRT Is a Potential Predictive Factor for the Response to S-1 in Gastric Cancer

Li¹,

Leong²,

Yuan³

et al. 2013

JCT

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Objective: To analyze the impact of mRNA expression of oral fluoropyrimidine (S-1) metabolism (thymidylate synthase, dihydropyrimidine dehydrogenase, thymidine phosphorylase, and orotate phosphoribosyltransferase [OPRT]), on treatment outcomes in locally advanced gastric cancer patients receiving preoperative S-1 combined with oxaliplatin chemotherapy. Methods: Preoperative stage III gastric cancer patients received S-1 (80 mg/m²/day; days 1-14) and oxaliplatin (130 mg/m²; day 1) every 3 weeks and subsequently received gastrectomy with D1/D2 lymphadenectomy. Paired tumor and normal fresh frozen tissues were collected to evaluate mRNA levels of thymidylate synthase, thymidine phosphorylase, dihydropyrimidine dehydrogenase, and orotate phosphoribosyltransferase using quantitative reverse-transcriptase polymerase chain reaction. Results: Between December 2009 and October 2010, thirty-five patients were enrolled in this study. 24 (68.5%) patients had clinical tumor response and 10 (28.6%) patients achieved histological response. Quantitative reverse-transcriptase polymerase chain reaction results showed that orotate phosphoribo-syltransferase (OPRT) mRNA expression was significantly higher in histological responders than non-responders (3.75 vs. 1.81, P = 0.005). Diffuse-type gastric cancer patients demonstrated higher orotate phosphoribosyltransferase (OPRT) expression levels than intestinal-type ones (2.79 vs. 1.60, P = 0.014). Similar results were not found when comparing thymidylate synthase, thymidine phosphorylase and dihydropyrimidine dehydrogenase expression levels. Conclusion: Orotate phosphoribosyltransferase (OPRT) expression level may be a potential predictive biomarker in advanced gastric cancer patients treated with oral fluoropyrimidine (S-1) based chemotherapy. Mini Abstract: Orotate phosphoribosyltransferase (OPRT) expression level may be a potential predictive biomarker in advanced gastric cancer patients treated with oral fluoropyrimidine (S-1) based chemotherapy.

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“…In contrast, recent trials of new anticancer chemotherapeutic agents, administered both individually and in combination, have shown that certain systemic chemotherapy regimens such as oral S-1 (a fluoropyrimidine) and oxaliplatin with low-dose leucovorin and bolus and continuous infusion 5-fluorouracil (modified FOLFOX-4) may also be effective for gastric malignant ascites [16,[25][26][27][28]. Paclitaxel is regarded as an active agent, with previous reports indicating that weekly paclitaxel has fewer adverse events and a better safety profile than tri-weekly paclitaxel and may be safely administered to patients with advanced gastric cancer [5][6][7]29].…”

Section: Validity Of Cbr-gc As a Measure Of Response To Treatment In mentioning

confidence: 99%

Assessing clinical benefit response in the treatment of gastric malignant ascites with non-measurable lesions: a multicenter phase II trial of paclitaxel for malignant ascites secondary to advanced/recurrent gastric cancer

et al. 2011

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A phase II study of combined chemotherapy with methotrexate, 5-fluorouracil, and low-dose cisplatin (MFP) for histologically diffuse-type advanced and recurrent gastric cancer (KDOG9501)

Cited by 7 publications

References 28 publications

SWI/SNF Activity Is Required for the Repression of Deoxyribonucleotide Triphosphate Metabolic Enzymes via the Recruitment of mSin3B

SWI/SNF Activity Is Required for the Repression of Deoxyribonucleotide Triphosphate Metabolic Enzymes via the Recruitment of mSin3B

OPRT Is a Potential Predictive Factor for the Response to S-1 in Gastric Cancer

Assessing clinical benefit response in the treatment of gastric malignant ascites with non-measurable lesions: a multicenter phase II trial of paclitaxel for malignant ascites secondary to advanced/recurrent gastric cancer

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