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https://www.readbyqxmd.com/read/27703008/the-role-of-folate-transport-in-antifolate-drug-action-in-trypanosoma-brucei
#1
Simon Dewar, Natasha Sienkiewicz, Han B Ong, Richard J Wall, David Horn, Alan H Fairlamb
The aim of this study was to identify and characterize mechanisms of resistance to antifolate drugs in African trypanosomes. Genome-wide RNAi library screens were undertaken in bloodstream form Trypanosoma brucei exposed to the antifolates methotrexate and raltitrexed. In conjunction with drug susceptibility and folate transport studies, RNAi knockdown was used to validate the functions of the putative folate transporters. The transport kinetics of folate and methotrexate were further characterized in whole cells...
November 18, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27649373/widespread-perturbation-of-function-structure-and-dynamics-by-a-conservative-single-atom-substitution-in-thymidylate-synthase
#2
Paul J Sapienza, Andrew L Lee
Thymidylate synthase (TSase) is responsible for synthesizing the sole de novo source of dTMP in all organisms. TSase is a drug target, and as such, it has been well studied in terms of both structure and reaction mechanism. Cysteine 146 in Escherichia coli TSase is universally conserved because it serves as the nucleophile in the enzyme mechanism. Here we use the C146S mutation to probe the role of the sulfur atom in early events in the catalytic cycle beyond serving as the nucleophile. Surprisingly, the single-atom substitution severely decreases substrate binding affinity, and the unfavorable ΔΔG°bind is comprised of roughly equal enthalpic and entropic components at 25 °C...
October 11, 2016: Biochemistry
https://www.readbyqxmd.com/read/27466517/concurrent-chemoradiation-with-concomitant-boost-in-locally-advanced-rectal-cancer-a-phase-ii-study
#3
Vincenzo Picardi, Francesco Deodato, Alessandra Guido, Lucia Giaccherini, Gabriella Macchia, Maria A Gambacorta, Alessandra Arcelli, Andrea Farioli, Francesco Cellini, Dajana Cuicchi, Francesca DI Fabio, Gilberto Poggioli, Andrea Ardizzoni, Giovanni Frezza, Savino Cilla, Luciana Caravatta, Vincenzo Valentini, Lorenzo Fuccio, Alessio G Morganti
AIM: The aim of this study was to evaluate the pathological response of locally advanced rectal cancer after preoperative concurrent two-drug chemotherapy and intensified radiation therapy (RT) with concomitant boost. PATIENTS AND METHODS: Patients with T4 tumor or local recurrence were included. A trial based on two-stage Simon's design was planned. RT was performed with 3D-conformal technique. The dose to the mesorectum and pelvic lymph nodes was 45 Gy (1.8 Gy/fraction)...
August 2016: Anticancer Research
https://www.readbyqxmd.com/read/27318567/enhanced-electrochemical-sensing-of-leukemia-cells-using-drug-lipid-co-immobilized-on-the-conducting-polymer-layer
#4
N G Gurudatt, M Halappa Naveen, Changill Ban, Yoon-Bo Shim
Electrochemical biosensors using five anticancer drug and lipid molecules attached on the conducting polymer layer to obtain the orientation of drug molecules toward cancer cells, were evaluated as sensing materials and their performances were compared. Conjugation of the drug molecules with a lipid, phosphatidylcholine (PC) has enhanced the sensitivity towards leukemia cells and differentiates cancer cells from normal cells. The composition of each layer of sensor probe was confirmed by electrochemical and surface characterization experiments...
December 15, 2016: Biosensors & Bioelectronics
https://www.readbyqxmd.com/read/27175479/trypanosoma-brucei-dhfr-ts-revisited-characterisation-of-a-bifunctional-and-highly-unstable-recombinant-dihydrofolate-reductase-thymidylate-synthase
#5
Marc W Gibson, Simon Dewar, Han B Ong, Natasha Sienkiewicz, Alan H Fairlamb
Bifunctional dihydrofolate reductase-thymidylate synthase (DHFR-TS) is a chemically and genetically validated target in African trypanosomes, causative agents of sleeping sickness in humans and nagana in cattle. Here we report the kinetic properties and sensitivity of recombinant enzyme to a range of lipophilic and classical antifolate drugs. The purified recombinant enzyme, expressed as a fusion protein with elongation factor Ts (Tsf) in ThyA- Escherichia coli, retains DHFR activity, but lacks any TS activity...
May 2016: PLoS Neglected Tropical Diseases
https://www.readbyqxmd.com/read/27145327/raltitrexed-plus-oxaliplatin-based-transarterial-chemoembolization-in-patients-with-unresectable-hepatocellular-carcinoma
#6
Chang Zhao, Liwei Fan, Feng Qi, Shengqiu Ou, Lei Yu, Xiaoyu Yi, Bingqiang Ni, Zhiyong Zheng, Jianxun Lu, Chengwen Zhang, Changsheng Chen, Xiong Lu, Lin Cheng, Tianlian Hu, Yilong Ma
Raltitrexed has shown efficacy and safety in many tumor types; however, the clinical data on the treatment of hepatocellular carcinoma is rare. In this report, we aim to assess the efficacy and safety of raltitrexed plus oxaliplatin (OXA)-based transarterial chemoembolization (TACE) in patients with unresectable hepatocellular carcinoma (uHCC). Patients with uHCC were recruited from multi-centers in China and assigned randomly to raltitrexed+OXA-based (n=76), fluorouracil+OXA-based (n=76), and doxorubicin+OXA-based (n=75) TACE treatment...
August 2016: Anti-cancer Drugs
https://www.readbyqxmd.com/read/27098147/raltitrexed-inhibits-hepg2-cell-proliferation-via-g0-g1-cell-cycle-arrest
#7
Hongwei Zhao, Yubao Zhang, Jianmin Sun, Chao Zhan, Liang Zhao
Raltitrexed (RTX) is an antimetabolite drug used as a chemotherapeutic agent for treating colorectal cancer, malignant mesothelioma, and gastric cancer. The antitumor capacity of RTX is attributed to its inhibitory activity on thymidylate synthase (TS), a key enzyme in the synthesis of DNA precursors. The current study is aimed at investigating the potential antitumor effects of RTX in liver cancer. Using the HepG2 cell line as an in vitro model of liver cancer, we evaluated the effects of RTX on cell proliferation employing both a WST-8 assay and a clone formation efficiency assay...
2016: Oncology Research
https://www.readbyqxmd.com/read/26780987/kat5-tip60-is-a-potential-therapeutic-target-in-malignant-pleural-mesothelioma
#8
Sian Cregan, Lauran McDonagh, Yun Gao, Martin P Barr, Kenneth J O'Byrne, Stephen P Finn, Sinead Cuffe, Steven G Gray
Malignant pleural mesothelioma (MPM) is a rare aggressive cancer of the pleura. Asbestos exposure (through inhalation) is the most well established risk factor for mesothelioma. The current standard of care for patients suffering from MPM is a combination of cisplatin and pemetrexed (or alternatively cisplatin and raltitrexed). Most patients, however, die within 24 months of diagnosis. New therapies are therefore urgently required for this disease. Lysine acetyltransferases (KATs) including KAT5 have been linked with the development of cisplatin resistance...
March 2016: International Journal of Oncology
https://www.readbyqxmd.com/read/26779722/laparoscopic-hyperthermic-intraperitoneal-perfusion-chemotherapy-for-patients-with-malignant-ascites-secondary-to-unresectable-gastric-cancer
#9
RANDOMIZED CONTROLLED TRIAL
Ming-Chen Ba, Hui Long, Xiang-Liang Zhang, Yuan-Feng Gong, Yun-Qiang Tang, Yin-Bing Wu, Fei-Hong Yu, Shu-Zhong Cui
BACKGROUND: To compare the efficacy of three chemotherapeutic combinations for laparoscopic hyperthermic intraperitoneal perfusion chemotherapy (HIPPC) in the treatment of malignant ascites secondary to unresectable gastric cancer (GC). MATERIALS AND METHODS: From January 2010 to December 2013, 38 GC patients were randomly divided into three groups and treated by laparoscopic HIPPC with one of the three following chemotherapy combinations: raltitrexed (Ra) with oxaliplatin [trans-(±)-diaminocyclohexane oxalatoplatinum (l-OHP)], Ra with cisplatin (DDP), and Ra with mitomycin C (MMC)...
January 2016: Journal of Laparoendoscopic & Advanced Surgical Techniques. Part A
https://www.readbyqxmd.com/read/26656372/the-malignant-transformation-of-retrorectal-cystic-hamartomas-with-blood-irregular-antibodies-positive-a-case-report
#10
Xiang-Rong Zhao, Chao Gao, Yong Zhang, Yong-Hua Yu
Retrorectal cystic hamartomas are rare congenital presacral lesions and malignancy is extremely rare. Although surgical excision is the essential for treatment, a unique feature of our case compared with previously reported tailgut cysts is that this patient's blood irregular antibodies are positive with higher operational risks.A 44-year-old woman presented to our department complaining of pelvic and perineal pain for 6 months. Computed tomography (CT) scan of the abdomen and pelvis demonstrated a well-demarcated hypodense, multilocular cystic lesion, 10 cm in size, in the presacral region of the right of the midline...
December 2015: Medicine (Baltimore)
https://www.readbyqxmd.com/read/26630264/structure-of-the-varicella-zoster-virus-thymidylate-synthase-establishes-functional-and-structural-similarities-as-the-human-enzyme-and-potentiates-itself-as-a-target-of-brivudine
#11
Kelly Hew, Sue-Li Dahlroth, Saranya Veerappan, Lucy Xin Pan, Tobias Cornvik, Pär Nordlund
Varicella zoster virus (VZV) is a highly infectious human herpesvirus that is the causative agent for chicken pox and shingles. VZV encodes a functional thymidylate synthase (TS), which is the sole enzyme that produces dTMP from dUMP de novo. To study substrate binding, the complex structure of TSVZV with dUMP was determined to a resolution of 2.9 Å. In the absence of a folate co-substrate, dUMP binds in the conserved TS active site and is coordinated similarly as in the human encoded TS (TSHS) in an open conformation...
2015: PloS One
https://www.readbyqxmd.com/read/26494862/genomically-incorporated-5-fluorouracil-that-escapes-ung-initiated-base-excision-repair-blocks-dna-replication-and-activates-homologous-recombination
#12
Amelia M Huehls, Catherine J Huntoon, Poorval M Joshi, Carly A Baehr, Jill M Wagner, Xiaoxiao Wang, Marietta Y Lee, Larry M Karnitz
5-Fluorouracil (5-FU) and its metabolite 5-fluorodeoxyuridine (FdUrd, floxuridine) are chemotherapy agents that are converted to 5-fluorodeoxyuridine monophosphate (FdUMP) and 5-fluorodeoxyuridine triphosphate (FdUTP). FdUMP inhibits thymidylate synthase and causes the accumulation of uracil in the genome, whereas FdUTP is incorporated by DNA polymerases as 5-FU in the genome; however, it remains unclear how either genomically incorporated U or 5-FU contributes to killing. We show that depletion of the uracil DNA glycosylase (UNG) sensitizes tumor cells to FdUrd...
January 2016: Molecular Pharmacology
https://www.readbyqxmd.com/read/26320185/critical-role-of-bevacizumab-scheduling-in-combination-with-pre-surgical-chemo-radiotherapy-in-mri-defined-high-risk-locally-advanced-rectal-cancer-results-of-the-branch-trial
#13
Antonio Avallone, Biagio Pecori, Franco Bianco, Luigi Aloj, Fabiana Tatangelo, Carmela Romano, Vincenza Granata, Pietro Marone, Alessandra Leone, Gerardo Botti, Antonella Petrillo, Corradina Caracò, Vincenzo R Iaffaioli, Paolo Muto, Giovanni Romano, Pasquale Comella, Alfredo Budillon, Paolo Delrio
BACKGROUND: We have previously shown that an intensified preoperative regimen including oxaliplatin plus raltitrexed and 5-fluorouracil/folinic acid (OXATOM/FUFA) during preoperative pelvic radiotherapy produced promising results in locally advanced rectal cancer (LARC). Preclinical evidence suggests that the scheduling of bevacizumab may be crucial to optimize its combination with chemo-radiotherapy. PATIENTS AND METHODS: This non-randomized, non-comparative, phase II study was conducted in MRI-defined high-risk LARC...
October 6, 2015: Oncotarget
https://www.readbyqxmd.com/read/25847479/determinants-of-the-activities-of-antifolates-delivered-into-cells-by-folate-receptor-mediated-endocytosis
#14
Rongbao Zhao, Michele Visentin, I David Goldman
PURPOSE: Elements in the endocytic process that are determinants of the activities of antifolates delivered by folate-receptor alpha (FRα) were explored. METHODS: Antifolate growth inhibition was assessed with a 1- or 5-day exposure in reduced folate carrier-null HeLa cell lines that express a high level of FRα in the presence or absence of the proton-coupled folate transporter (PCFT). pH-dependent rates of dissociation from FRα were also determined. RESULTS: With a 1-day drug exposure which is relevant to the pulse clinical administration of these drugs, FRα expression enhanced raltitrexed activity and modestly enhanced ZD9331 activity, but did not significantly augment the activity of pemetrexed or lomotrexol...
June 2015: Cancer Chemotherapy and Pharmacology
https://www.readbyqxmd.com/read/25817092/-interstitial-lung-disease-induced-by-raltitrexed-oxaliplatin-based-chemotherapy-for-colorectal-cancer-a-case-report
#15
LETTER
Montserrat Carreres-Prieto, David López-Sisamón, Laura Layos-Romero
No abstract text is available yet for this article.
March 2015: Farmacia Hospitalaria
https://www.readbyqxmd.com/read/25758781/alterations-of-dna-repair-genes-in-the-nci-60-cell-lines-and-their-predictive-value-for-anticancer-drug-activity
#16
Fabricio G Sousa, Renata Matuo, Sai-Wen Tang, Vinodh N Rajapakse, Augustin Luna, Chris Sander, Sudhir Varma, Paul H G Simon, James H Doroshow, William C Reinhold, Yves Pommier
Loss of function of DNA repair (DNAR) genes is associated with genomic instability and cancer predisposition; it also makes cancer cells reliant on a reduced set of DNAR pathways to resist DNA-targeted therapy, which remains the core of the anticancer armamentarium. Because the landscape of DNAR defects across numerous types of cancers and its relation with drug activity have not been systematically examined, we took advantage of the unique drug and genomic databases of the US National Cancer Institute cancer cell lines (the NCI-60) to characterize 260 DNAR genes with respect to deleterious mutations and expression down-regulation; 169 genes exhibited a total of 549 function-affecting alterations, with 39 of them scoring as putative knockouts across 31 cell lines...
April 2015: DNA Repair
https://www.readbyqxmd.com/read/25677305/screening-and-in-vitro-testing-of-antifolate-inhibitors-of-human-cytosolic-serine-hydroxymethyltransferase
#17
Alessandro Paiardini, Alessio Fiascarelli, Serena Rinaldo, Frederick Daidone, Giorgio Giardina, David R Koes, Alessia Parroni, Giulia Montini, Marina Marani, Alessio Paone, Lee A McDermott, Roberto Contestabile, Francesca Cutruzzolà
Metabolic reprogramming of tumor cells toward serine catabolism is now recognized as a hallmark of cancer. Serine hydroxymethyltransferase (SHMT), the enzyme providing one-carbon units by converting serine and tetrahydrofolate (H4 PteGlu) to glycine and 5,10-CH2 -H4 PteGlu, therefore represents a target of interest in developing new chemotherapeutic drugs. In this study, 13 folate analogues under clinical evaluation or in therapeutic use were in silico screened against SHMT, ultimately identifying four antifolate agents worthy of closer evaluation...
March 2015: ChemMedChem
https://www.readbyqxmd.com/read/25562513/inhibition-of-thymidylate-synthase-by-2-2-difluoro-2-deoxycytidine-gemcitabine-and-its-metabolite-2-2-difluoro-2-deoxyuridine
#18
Richard J Honeywell, Veronique W T Ruiz van Haperen, Gijsbert Veerman, Kees Smid, Godefridus J Peters
2',2'-Difluoro-2'-deoxycytidine (dFdC, gemcitabine) is a cytidine analogue active against several solid tumor types, such as ovarian, pancreatic and non-small cell lung cancer. The compound has a complex mechanism of action. Because of the structural similarity of one metabolite of dFdC, dFdUMP, with the natural substrate for thymidylate synthase (TS) dUMP, we investigated whether dFdC and its deamination product 2',2'-difluoro-2'-deoxyuridine (dFdU) would inhibit TS. This study was performed using two solid tumor cell lines: the human ovarian carcinoma cell line A2780 and its dFdC-resistant variant AG6000...
March 2015: International Journal of Biochemistry & Cell Biology
https://www.readbyqxmd.com/read/25547003/preliminary-investigation-of-intraperitoneal-raltitrexed-in-patients-with-gastric-cancer
#19
RANDOMIZED CONTROLLED TRIAL
Ping Zhao, Zhi Ding, Lingchao Tang, Xiang Zhou
BACKGROUND: Peritoneal implantation metastasis of gastric cancer is the major reason for cancer recurrence after radical operations. As a new chemotherapeutic agent, raltitrexed has been widely used in intravenous chemotherapy for many kinds of cancers. However, no study has reported the efficacy and safety of raltitrexed in intraperitoneal chemotherapy. This study aimed to explore the safety of intraperitoneal chemotherapy with raltitrexed during gastric cancer operation compared to normal saline (NS) rinsing of the abdominal cavity...
2014: World Journal of Surgical Oncology
https://www.readbyqxmd.com/read/25491626/the-role-of-raltitrexed-cisplatin-with-concurrent-radiation-therapy-in-treating-advanced-cervical-cancer
#20
X-Y Li, L Liu, X-M Xie, C Zhou
OBJECTIVE: To explore the effectiveness and safety of raltitrexed/cisplatin with concurrent radiotherapy in treating of patients with advanced cervical cancer. PATIENTS AND METHODS: Sixty-five patients with stage IIB-IVA cervical cancer enrolled in this study, received raltitrexed/cisplatin with concurrent radiotherapy. The treatment consisted of raltitrexed 3 mg/m2 iv 15 min, d1; cisplatin 60 mg/m2 iv 60 min, d1, and pelvic radiotherapy, using three-dimensional conformal radiotherapy...
November 2014: European Review for Medical and Pharmacological Sciences
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