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Structure and dynamics of AMPA receptor GluA2 in resting, pre-open, and desensitized states.
Dürr KL, Chen L, Stein RA, De Zorzi R, Folea IM, Walz T, Mchaourab HS, Gouaux E
(2014) Cell 158: 778-792
MeSH Terms: Animals, Cryoelectron Microscopy, Crystallography, X-Ray, Fluorouracil, Gene Knockout Techniques, Kainic Acid, Molecular Structure, Nuclear Magnetic Resonance, Biomolecular, Protein Structure, Tertiary, Rats, Receptors, AMPA
Show Abstract · Added February 19, 2015
Ionotropic glutamate receptors (iGluRs) mediate the majority of fast excitatory signaling in the nervous system. Despite the profound importance of iGluRs to neurotransmission, little is known about the structures and dynamics of intact receptors in distinct functional states. Here, we elucidate the structures of the intact GluA2 AMPA receptor in an apo resting/closed state, in an activated/pre-open state bound with partial agonists and a positive allosteric modulator, and in a desensitized/closed state in complex with fluorowilliardiine. To probe the conformational properties of these states, we carried out double electron-electron resonance experiments on cysteine mutants and cryoelectron microscopy studies. We show how agonist binding modulates the conformation of the ligand-binding domain "layer" of the intact receptors and how, upon desensitization, the receptor undergoes large conformational rearrangements of the amino-terminal and ligand-binding domains. We define mechanistic principles by which to understand antagonism, activation, and desensitization in AMPA iGluRs.
Copyright © 2014 Elsevier Inc. All rights reserved.
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11 MeSH Terms
Comparison of FOLFIRI with or without cetuximab in patients with resected stage III colon cancer; NCCTG (Alliance) intergroup trial N0147.
Huang J, Nair SG, Mahoney MR, Nelson GD, Shields AF, Chan E, Goldberg RM, Gill S, Kahlenberg MS, Quesenberry JT, Thibodeau SN, Smyrk TC, Grothey A, Sinicrope FA, Webb TA, Farr GH, Pockaj BA, Berenberg JL, Mooney M, Sargent DJ, Alberts SR, Alliance for Clinical Trials in Oncology
(2014) Clin Colorectal Cancer 13: 100-9
MeSH Terms: Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Humanized, Antineoplastic Combined Chemotherapy Protocols, Camptothecin, Cetuximab, Chemotherapy, Adjuvant, Colonic Neoplasms, Disease-Free Survival, Female, Fluorouracil, Follow-Up Studies, Humans, Leucovorin, Male, Middle Aged, Mutation, Neoplasm Staging, Proto-Oncogene Proteins, Proto-Oncogene Proteins p21(ras), Survival Rate, Treatment Outcome, ras Proteins
Show Abstract · Added March 28, 2014
BACKGROUND - Two arms with FOLFIRI, with or without cetuximab, were initially included in the randomized phase III intergroup clinical trial NCCTG (North Central Cancer Treatment Group) N0147. When other contemporary trials demonstrated no benefit to using irinotecan as adjuvant therapy, the FOLFIRI-containing arms were discontinued. We report the clinical outcomes for patients randomized to FOLFIRI with or without cetuximab.
PATIENTS AND METHODS - After resection, patients were randomized to 12 biweekly cycles of FOLFIRI, with or without cetuximab. KRAS (Kirsten rat sarcoma viral oncogene homolog) mutation status was retrospectively determined in a central lab. The primary end point was disease-free survival (DFS). Secondary end points included overall survival (OS) and toxicity.
RESULTS - One hundred and six patients received FOLFIRI and 40 received FOLFIRI plus cetuximab. Median follow-up was 5.95 years (range, 0.1-7.0 years). The addition of cetuximab showed a trend toward improved DFS (hazard ratio [HR], 0.53; 95% CI, 0.26-1.1; P = .09) and OS (HR, 0.45; 95% CI, 0.17-1.16; P = .10) in the overall group, regardless of KRAS status, and in patients with wild type KRAS. Grade ≥ 3 nonhematologic adverse effects were significantly increased in the cetuximab versus FOLFIRI-alone arm (68% vs. 46%; P = .02). Adjuvant FOLFIRI resulted in a 3-year DFS less than that expected for FOLFOX.
CONCLUSION - In this small randomized subset of patients with resected stage III colon cancer, the addition of cetuximab to FOLFIRI was associated with a nonsignificant trend toward improved DFS and OS. Nevertheless, considering the limitations of this analysis, FOLFOX without the addition of a biologic agent remains the standard of care for adjuvant therapy in resected stage III colon cancer.
Copyright © 2014 Elsevier Inc. All rights reserved.
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24 MeSH Terms
Loss of Smad4 in colorectal cancer induces resistance to 5-fluorouracil through activating Akt pathway.
Zhang B, Zhang B, Chen X, Bae S, Singh K, Washington MK, Datta PK
(2014) Br J Cancer 110: 946-57
MeSH Terms: Animals, Antimetabolites, Antineoplastic, Cell Cycle Proteins, Cell Line, Tumor, Cell Movement, Cell Proliferation, Cell Survival, Chromones, Colorectal Neoplasms, Drug Resistance, Neoplasm, Enzyme Activation, Enzyme Inhibitors, Fluorouracil, Humans, Inhibitor of Apoptosis Proteins, Mice, Mice, Inbred BALB C, Morpholines, Neoplasm Invasiveness, Neoplasm Metastasis, Neoplasm Transplantation, Neovascularization, Pathologic, Phosphatidylinositol 3-Kinase, Phosphatidylinositol 3-Kinases, Phosphorylation, Proteins, Proto-Oncogene Proteins c-akt, Proto-Oncogene Proteins c-bcl-2, Repressor Proteins, Retinoblastoma Protein, Smad4 Protein, Survivin, Up-Regulation, Vascular Endothelial Growth Factor A, Wound Healing, Xenograft Model Antitumor Assays
Show Abstract · Added April 12, 2016
BACKGROUND - Higher frequency of Smad4 inactivation or loss of expression is observed in metastasis of colorectal cancer (CRC) leading to unfavourable survival and contributes to chemoresistance. However, the molecular mechanism of how Smad4 regulates chemosensitivity of CRC is unknown.
METHODS - We evaluated how the loss of Smad4 in CRC enhanced chemoresistance to 5-fluorouracil (5-FU) using two CRC cell lines in vitro and in vivo. Immunoblotting with cell and tumour lysates and immunohistochemical analyses with tissue microarray were performed.
RESULTS - Knockdown or loss of Smad4 induced tumorigenicity, migration, invasion, angiogenesis, metastasis, and 5-FU resistance. Smad4 expression in mouse tumours regulated cell-cycle regulatory proteins leading to Rb phosphorylation. Loss of Smad4 activated Akt pathway that resulted in upregulation of anti-apoptotic proteins, Bcl-2 and Bcl-w, and Survivin. Suppression of phosphatidylinositol-3-kinase (PI3K)/Akt pathway by LY294002 restored chemosensitivity of Smad4-deficient cells to 5-FU. Vascular endothelial growth factor-induced angiogenesis in Smad4-deficient cells might also lead to chemoresistance. Low levels of Smad4 expression in CRC tissues correlated with higher levels of Bcl-2 and Bcl-w and with poor overall survival as observed in immunohistochemical staining of tissue microarrays.
CONCLUSION - Loss of Smad4 in CRC patients induces resistance to 5-FU-based therapy through activation of Akt pathway and inhibitors of this pathway may sensitise these patients to 5-FU.
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36 MeSH Terms
Beyond exon 2--the developing story of RAS mutations in colorectal cancer.
Berlin J
(2013) N Engl J Med 369: 1059-60
MeSH Terms: Antibodies, Monoclonal, Antineoplastic Combined Chemotherapy Protocols, Colorectal Neoplasms, ErbB Receptors, Fluorouracil, Genes, ras, Humans, Leucovorin, Organoplatinum Compounds, Panitumumab, Proto-Oncogene Proteins, Proto-Oncogene Proteins B-raf, Proto-Oncogene Proteins p21(ras), ras Proteins
Added March 20, 2014
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14 MeSH Terms
Imaging analysis of hepatoblastoma resectability across neoadjuvant chemotherapy.
Murphy AJ, Ayers GD, Hilmes MA, Mukherjee K, Wilson KJ, Allen WM, Fernandez-Pineda I, Shinall MC, Zhao Z, Furman WL, McCarville MB, Davidoff AM, Lovvorn HN
(2013) J Pediatr Surg 48: 1239-48
MeSH Terms: Algorithms, Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols, Chemotherapy, Adjuvant, Cisplatin, Clinical Protocols, Doxorubicin, Female, Fluorouracil, Hepatectomy, Hepatoblastoma, Humans, Image Interpretation, Computer-Assisted, Liver Neoplasms, Magnetic Resonance Imaging, Male, Models, Statistical, Neoadjuvant Therapy, Retrospective Studies, Tomography, X-Ray Computed, Treatment Outcome, Tumor Burden, Vincristine
Show Abstract · Added December 26, 2013
PURPOSE - Hepatoblastomas often require neoadjuvant chemotherapy to facilitate partial hepatectomy, which necessitates freedom of tumor borders from the confluence of hepatic veins (COHV), portal vein bifurcation (PVB), and retrohepatic inferior vena cava (IVC). This study aimed to clarify the effect of incremental neoadjuvant cycles on the AHEP0731 protocol criteria of hepatoblastoma resectability.
METHODS - Hepatoblastoma responses to neoadjuvant chemotherapy were analyzed among patients (n=23) treated at two children's hospitals between 1996 and 2010. Using digital imaging data, ellipsoid and point-based models were created to measure tumor volume regression and respective distances from tumor borders nearest to the COHV, PVB, and IVC.
RESULTS - Hepatoblastoma volumes regressed with incremental neoadjuvant chemotherapy cycles (p<0.001). Although tumor borders regressed away from the COHV (p=0.008), on average only 1.1mm was gained. No change from tumor borders to the PVB was detected (p=0.102). Distances from tumor borders to the IVC remained stable at one hospital (p=0.612), but increased only 0.15 mm every 10 days of therapy at the other (p=0.002). Neoadjuvant chemotherapy induced slightly more tumors to meet the threshold vascular margin of 1cm (baseline to completion): COHV, 11 (47.8%) to 17 (73.9%; p=0.058); PVB, 11 (47.8%) to 15 (65.2%; p=0.157); and IVC, 4 (17.4%) to 10 (43.5%; p=0.034). No differences were detected in demographic or disease-specific characteristics between patients who did or did not achieve this 1-cm margin after conclusion of chemotherapy.
CONCLUSION - Hepatoblastoma volumes regress significantly with increasing neoadjuvant chemotherapy cycles. However, tumors often remain anchored to the major hepatic vasculature, showing marginal improvement in resectability criteria.
Copyright © 2013 Elsevier Inc. All rights reserved.
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23 MeSH Terms
Aflibercept.
Ciombor KK, Berlin J, Chan E
(2013) Clin Cancer Res 19: 1920-5
MeSH Terms: Antineoplastic Combined Chemotherapy Protocols, Camptothecin, Clinical Trials, Phase II as Topic, Clinical Trials, Phase III as Topic, Colorectal Neoplasms, Disease-Free Survival, Fluorouracil, Humans, Irinotecan, Leucovorin, Neoplasm Metastasis, Organoplatinum Compounds, Oxaliplatin, Placenta Growth Factor, Pregnancy Proteins, Protein Binding, Randomized Controlled Trials as Topic, Receptors, Vascular Endothelial Growth Factor, Recombinant Fusion Proteins, Treatment Outcome, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factor B
Show Abstract · Added September 10, 2013
Aflibercept, an intravenously administered anti-VEGF and antiplacental growth factor (PlGF) agent, has recently been approved by the U.S. Food and Drug Administration in combination with 5-fluorouracil, leucovorin, and irinotecan (FOLFIRI) for the treatment of patients with metastatic colorectal cancer who have previously received an oxaliplatin-containing chemotherapy regimen. In the phase III VELOUR trial, aflibercept plus FOLFIRI statistically significantly prolonged both progression-free survival (PFS; median PFS for the aflibercept plus FOLFIRI arm was 6.90 vs. 4.67 months for the placebo-plus-FOLFIRI arm) and overall survival (median overall survival for the aflibercept-plus-FOLFIRI arm was 13.50 vs. 12.06 months for the placebo plus FOLFIRI arm), but grade 3 or 4 adverse events were more common with the addition of aflibercept. However, the addition of aflibercept to 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) in the phase II AFFIRM trial of first-line treatment of mCRC failed to improve PFS or response rate. As a decoy VEGF receptor, aflibercept (VEGF-Trap) has binding affinity for VEGF-A, VEGF-B, PlGF-1, and PlGF-2, and this is a mechanism of significant interest. Optimal strategies for incorporating aflibercept into treatment regimens that include other anti-VEGF and cytotoxic chemotherapeutic agents, as well as development of predictive biomarkers for treatment response, have yet to be defined.
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22 MeSH Terms
A randomized phase II trial of vismodegib versus placebo with FOLFOX or FOLFIRI and bevacizumab in patients with previously untreated metastatic colorectal cancer.
Berlin J, Bendell JC, Hart LL, Firdaus I, Gore I, Hermann RC, Mulcahy MF, Zalupski MM, Mackey HM, Yauch RL, Graham RA, Bray GL, Low JA
(2013) Clin Cancer Res 19: 258-67
MeSH Terms: Adult, Aged, Aged, 80 and over, Anilides, Antibodies, Monoclonal, Humanized, Antineoplastic Combined Chemotherapy Protocols, Bevacizumab, Camptothecin, Colorectal Neoplasms, Female, Fluorouracil, Humans, Leucovorin, Male, Maximum Tolerated Dose, Middle Aged, Neoplasm Metastasis, Organoplatinum Compounds, Proto-Oncogene Proteins, Proto-Oncogene Proteins p21(ras), Pyridines, Treatment Outcome, ras Proteins
Show Abstract · Added March 7, 2014
PURPOSE - Vismodegib, a Hedgehog pathway inhibitor, has preclinical activity in colorectal cancer (CRC) models. This trial assessed the efficacy, safety, and pharmacokinetics of adding vismodegib to first-line treatment for metastatic CRC (mCRC).
EXPERIMENTAL DESIGN - Patients were randomized to receive vismodegib (150 mg/day orally) or placebo, in combination with FOLFOX or FOLFIRI chemotherapy plus bevacizumab (5 mg/kg) every 2 weeks until disease progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS). Key secondary objectives included evaluation of predictive biomarkers and pharmacokinetic drug interactions.
RESULTS - A total of 199 patients with mCRC were treated on protocol (124 FOLFOX, 75 FOLFIRI). The median PFS hazard ratio (HR) for vismodegib treatment compared with placebo was 1.25 (90% CI: 0.89-1.76; P = 0.28). The overall response rates for placebo-treated and vismodegib-treated patients were 51% (90% CI: 43-60) and 46% (90% CI: 37-55), respectively. No vismodegib-associated benefit was observed in combination with either FOLFOX or FOLFIRI. Increased tumor tissue Hedgehog expression did not predict clinical benefit. Grade 3 to 5 adverse events reported for more than 5% of patients that occurred more frequently in the vismodegib-treated group were fatigue, nausea, asthenia, mucositis, peripheral sensory neuropathy, weight loss, decreased appetite, and dehydration. Vismodegib did not alter the pharmacokinetics of FOLFOX, FOLFIRI, or bevacizumab.
CONCLUSIONS - Vismodegib does not add to the efficacy of standard therapy for mCRC. Compared with placebo, treatment intensity was lower for all regimen components in vismodegib-treated patients, suggesting that combined toxicity may have contributed to lack of efficacy.
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23 MeSH Terms
Identification of novel germline polymorphisms governing capecitabine sensitivity.
O'Donnell PH, Stark AL, Gamazon ER, Wheeler HE, McIlwee BE, Gorsic L, Im HK, Huang RS, Cox NJ, Dolan ME
(2012) Cancer 118: 4063-73
MeSH Terms: Antimetabolites, Antineoplastic, Capecitabine, Deoxycytidine, European Continental Ancestry Group, Female, Fluorouracil, Genome-Wide Association Study, Humans, Male, Polymorphism, Single Nucleotide, Population Surveillance
Show Abstract · Added February 22, 2016
BACKGROUND - Capecitabine, an oral 5-fluorouracil (5-FU) prodrug, is widely used in the treatment of breast, colorectal, and gastric cancers. To guide the selection of patients with potentially the greatest benefit of experiencing antitumor efficacy, or, alternatively, of developing toxicities, identifying genomic predictors of capecitabine sensitivity could permit its more informed use.
METHODS - The objective of this study was to perform capecitabine sensitivity genome-wide association studies (GWAS) using 503 well genotyped human cell lines from individuals representing multiple different world populations. A meta-analysis that included all ethnic populations then enabled the identification of novel germline determinants (single nucleotide polymorphisms [SNPs]) of capecitabine susceptibility.
RESULTS - First, an intrapopulation GWAS of Caucasian individuals identified reference SNP 4702484 (rs4702484) (within adenylate cyclase 2 [ADCY2]) at a level reaching genome-wide significance (P = 5.2 × 10(-8) ). This SNP is located upstream of the 5 methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR) gene, and it is known that the enzyme for MTRR is involved in the methionine-folate biosynthesis and metabolism pathway, which is the primary target of 5-FU-related compounds, although the authors were unable to identify a direct relation between rs4702484 and MTRR expression in a tested subset of cells. In the meta-analysis, 4 SNPs comprised the top hits, which, again, included rs4702484 and 3 additional SNPs (rs8101143, rs576523, and rs361433) that approached genome-wide significance (P values from 1.9 × 10(-7) to 8.8 × 10(-7) ). The meta-analysis also identified 1 missense variant (rs11722476; serine to asparagine) within switch/sucrose nonfermentable-related, matrix-associated, actin-dependent regulator of chromatin (SMARCAD1), a novel gene for association with capecitabine/5-FU susceptibility.
CONCLUSIONS - Toward the goal of individualizing cancer chemotherapy, the current study identified novel SNPs and genes associated with capecitabine sensitivity that are potentially informative and testable in any patient regardless of ethnicity.
Copyright © 2011 American Cancer Society.
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11 MeSH Terms
Systemic combination therapy of intravenous continuous 5-fluorouracil and subcutaneous pegylated interferon alfa-2a for advanced hepatocellular carcinoma.
Uchino K, Obi S, Tateishi R, Sato S, Kanda M, Sato T, Arano T, Enooku K, Goto E, Masuzaki R, Nakagawa H, Asaoka Y, Kondo Y, Yamashiki N, Goto T, Shiina S, Omata M, Yoshida H, Koike K
(2012) J Gastroenterol 47: 1152-9
MeSH Terms: Adult, Aged, Aged, 80 and over, Antimetabolites, Antineoplastic, Antineoplastic Combined Chemotherapy Protocols, Antiviral Agents, Carcinoma, Hepatocellular, Cohort Studies, Female, Fluorouracil, Humans, Infusions, Intravenous, Injections, Subcutaneous, Interferon-alpha, Japan, Liver Neoplasms, Male, Middle Aged, Polyethylene Glycols, Recombinant Proteins, Retrospective Studies, Survival Rate, Treatment Outcome
Show Abstract · Added May 2, 2014
BACKGROUND - In Japan, sorafenib is now the first-line therapy for individuals with advanced hepatocellular carcinoma (HCC), but no other treatment is available for such patients. The aim of this study was to assess the efficacy and safety of combination therapy with systemic continuous intravenous infusion of 5-fluorouracil (5-FU) and subcutaneous peginterferon alfa-2a, which was used before sorafenib was introduced to Japan.
METHODS - Two hundred and twenty-three HCC patients, who were not amenable to curative surgery, percutaneous ablation, or transarterial chemoembolization (TACE), and for whom intraarterial chemotherapy was not indicated because of the presence of extrahepatic metastasis or stenosis of the common hepatic artery, received peginterferon alfa-2a (90 μg subcutaneously on days 1, 8, 15, and 22) and 5-FU (500 mg/day intravenously given continuously on days 1-5 and 8-12). We assessed their response to treatment and survival, and treatment safety.
RESULTS - The response rate was 9.4 % (including six patients with complete response) and the disease-control rate was 32.7 %. The median time to progression was 2.0 months. The overall median survival time was 6.5 months (Child-Pugh class A: 9.2 months vs. Child-Pugh class B: 2.8 months). In a multivariate analysis, Eastern Cooperative Oncology Group (ECOG) performance status >0, Child-Pugh class B, and the presence of macroscopic vascular invasion were independent predictors of poor prognosis. The major grade 3-4 adverse events were leucopenia (13.9 %) and thrombocytopenia (5.8 %). No treatment-related deaths occurred.
CONCLUSIONS - This combination therapy was well tolerated and showed promising efficacy. Further studies are needed to establish the usefulness of this treatment.
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23 MeSH Terms
Treatment of early-stage pancreatic cancer.
Castellanos EH, Cardin DB, Berlin JD
(2011) Oncology (Williston Park) 25: 182-9
MeSH Terms: Antineoplastic Combined Chemotherapy Protocols, Chemotherapy, Adjuvant, Clinical Trials as Topic, Deoxycytidine, Fluorouracil, Humans, Neoadjuvant Therapy, Pancreatic Neoplasms, Radiotherapy, Adjuvant
Show Abstract · Added March 18, 2014
Pancreatic cancer is the fourth leading cause of cancer death, and it is estimated that over 43,000 people would be diagnosed with and over 36,000 people would die of pancreatic cancer in the United States in 2010. Surgical resection remains the only chance for possible cure, but only 15% to 20% of patients newly diagnosed with pancreatic cancer are considered for surgical resection. Of these, the median five-year survival rate is still less than 20%, with most resections resulting in recurrent disease. This suggests that even seemingly resectable pancreatic cancer has microscopic systemic spread before operative intervention occurs. Both adjuvant and neoadjuvant therapies have been studied in an effort to improve survival for patients with resectable pancreatic cancer.
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9 MeSH Terms