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https://www.readbyqxmd.com/read/28927061/5fu-resistance-caused-by-reduced-fluoro-deoxyuridine-monophosphate-and-its-reversal-using-deoxyuridine
#1
Ryutaro Mori, Manabu Futamura, Toshiyuki Tanahashi, Yoshihiro Tanaka, Nobuhisha Matsuhashi, Kazuya Yamaguchi, Kazuhiro Yoshida
The mechanism of 5-fluorouracil (5FU) resistance was investigated, focusing on the level of thymidylate synthase (TS) ternary complex formed with fluoro-deoxyuridine monophosphate (FdUMP). MKN45 and 5FU-resistant MKN45/F2R cells were treated with 5FU and fluoro-deoxyuridine (FdU) in combination with deoxyuridine (dU) and thymidine (dT). Subsequently, the levels of ternary complex were determined by western blotting and the cell viability was calculated using an MTT assay. MKN45/F2R cells exhibited 5FU resistance (56...
September 2017: Oncology Letters
https://www.readbyqxmd.com/read/28697647/antimetabolites-in-the-treatment-of-advanced-pleural-mesothelioma-a-network-meta-analysis-of-randomized-clinical-trials
#2
Davide Tassinari, Chiara Cherubini, Emiliano Tamburini, Fabrizio Drudi, Maximilian Papi, Manuela Fantini, Luigi Lazzari-Agli, Sergio Sartori
An indirect comparison of cisplatin-pemetrexed (CP) and cisplatin-raltitrexed (CR) was performed. The Odds Ratios of 10, 15 and 20 month survival rate and response rate were assumed as indexes of efficacy; the Odds Ratio of grade III-IV side effects, and the absolute risk of overall, hematologic and non-hematologic toxicity, were assumed as indexes of safety. The outcomes of 352 patients were analysed. The Odds Ratios and 95% Confidence Interval (95% CI) of 10, 15 and 20 months survival rate and response rate were 1...
July 11, 2017: Journal of Chemotherapy
https://www.readbyqxmd.com/read/28634233/structural-analyses-of-human-thymidylate-synthase-reveal-a-site-that-may-control-conformational-switching-between-active-and-inactive-states
#3
COMPARATIVE STUDY
Dan Chen, Anna Jansson, Daniel Sim, Andreas Larsson, Pär Nordlund
Thymidylate synthase (TS) is the sole enzyme responsible for de novo biosynthesis of thymidylate (TMP) and is essential for cell proliferation and survival. Inhibition of human TS (hTS) has been extensively investigated for cancer chemotherapy, but several aspects of its activity and regulation are still uncertain. In this study, we performed comprehensive structural and biophysical studies of hTS using crystallography and thermal shift assay and provided the first detailed structural information on the conformational changes induced by ligand binding to the hTS active site...
August 11, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28628839/a-simple-and-fast-lc-ms-ms-method-with-a-very-high-sensitivity-for-the-measurement-of-raltitrexed-in-human-plasma
#4
Stefano Kim, Amaëlle Bisch, Damien Montange, Marie-Justine Paillard, Thierry Nguyen, Marine Jary, Marion Jacquin, Betsy Winkfield, Christophe Borg, Bernard Royer
Raltitrexed is a thymidylate synthase inhibitor that can be administered safely to patients with cardiovascular disease or dihydropyrimidine dehydrogenase deficiency, as opposed to 5FU. The recommended dose of 3mg/m(2) every 3 weeks often leads to toxicity. Interestingly, the 2mg/m(2) every 2 weeks dose appears to be less toxic. A pharmacokinetic trial was then performed by our team to investigate such phenomenon. However, there are currently, two main methods for RTX measurement described in the literature: a radioimmunoassay (RIA) and chromatographic-based methods with either UV or mass spectrometry detections...
August 15, 2017: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
https://www.readbyqxmd.com/read/28535418/a-study-of-peritoneal-metastatic-xenograft-model-of-colorectal-cancer-in-the-treatment-of-hyperthermic-intraperitoneal-chemotherapy-with-raltitrexed
#5
Cen Qiu, Yueqi Li, Xin Liang, Yingxue Qi, Yiyang Chen, Xianke Meng, Hongtu Zheng, Ye Xu, Sanjun Cai, Guoxiang Cai, Jianwen Liu
Peritoneal metastasis of colorectal cancer is one of the most incident and fateful diseases among relapse cases. It shows a certain resistance to systemic chemotherapy. The perfusion system in clinic is complex and hard to be used in fundamental researches. This study aims at evaluating the effect of an improved hyperthermic intraperitoneal chemotherapy with Raltitrexed used in tumor-bearing mice with peritoneal metastatic colorectal carcinoma. The results showed that no severe adverse effect was observed. All control animals developed extensive peritoneal and mesenteric metastatic nodes...
August 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/28456721/investigation-of-the-importance-of-multidrug-resistance-associated-protein-4-mrp4-abcc4-in-the-active-efflux-of-anionic-drugs-across-the-blood-brain-barrier
#6
Kayoko Kanamitsu, Hiroyuki Kusuhara, John D Schuetz, Kenji Takeuchi, Yuichi Sugiyama
The importance of multidrug resistance-associated protein 4 (Mrp4/Abcc4) in limiting the penetration of Mrp4 substrate compounds into the central nervous system across the blood-brain barrier was investigated using Mrp4(-/-) mice. Significant adenosine triphosphate-dependent uptake by MRP4 was observed for ochratoxin A, pitavastatin, raltitrexed (Km = 43.7 μM), pravastatin, cyclic guanosine monophosphate, 2,4-dichlorophenoxyacetate, and urate. The defect in the Mrp4 gene did not affect the brain-to-plasma ratio (Kp,brain) of quinidine and dantrolene...
April 27, 2017: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28415810/comparison-of-two-transarterial-chemoembolization-regimens-in-patients-with-unresectable-hepatocellular-carcinoma-raltitrexed-plus-oxaliplatin-versus-5-fluorouracil-plus-oxaliplatin
#7
Wei Cui, Wenzhe Fan, Qun Zhang, Jia Wen, Yonghui Huang, Jianyong Yang, Jiaping Li, Yu Wang
AIMS: To compare the safety and efficacy of TACE using raltitrexed, oxaliplatin and epirubicin with 5-fluorouracil, oxaliplatin and epirubicin for patients with unresectable hepatocelluar carcinoma. RESULTS: Median overall survival (OS) was 7.4 months in the raltitrexed group [95% confidence interval (CI): 5.4, 9.4) and 5.8 months in the control group (95% CI: 5.2, 6.4; P = 0.177). The median progression-free survival (PFS) time was significantly higher in the raltitrexed group (3...
March 16, 2017: Oncotarget
https://www.readbyqxmd.com/read/28293087/hepatic-artery-infusion-with-raltitrexed-or-5-fluorouracil-for-colorectal-cancer-liver-metastasis
#8
Jian-Hai Guo, Hang-Yu Zhang, Song Gao, Peng-Jun Zhang, Xiao-Ting Li, Hui Chen, Xiao-Dong Wang, Xu Zhu
AIM: To evaluate the efficiency and safety of hepatic artery infusion chemotherapy (HAIC) using raltitrexed or 5-fluorouracil for colorectal cancer (CRC) liver metastasis (CRCLM). METHODS: A retrospective analysis of patients with unresectable CRCLM who failed systemic chemotherapy and were subsequently treated with HAIC at our institute from May 2013 to April 2015 was performed. A total of 24 patients were treated with 5-fluorouracil, and 18 patients were treated with raltitrexed...
February 28, 2017: World Journal of Gastroenterology: WJG
https://www.readbyqxmd.com/read/28197626/kdm6a-and-kdm6b-altered-expression-in-malignant-pleural-mesothelioma
#9
Sian Cregan, Maeve Breslin, Gerard Roche, Sigrid Wennstedt, Lauren MacDonagh, Cinaria Albadri, Yun Gao, Kenneth J O'Byrne, Sinead Cuffe, Stephen P Finn, Steven G Gray
Malignant pleural mesothelioma (MPM) is a rare aggressive cancer of the pleura primarily associated with prior exposure to asbestos. 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. Inflammation is thought to be a key element in the pathogenesis of MPM, and recently Kdm6 family members (Kdm6a and Kdm6b) have been identified as playing important roles in inflammatory processes...
March 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/28121946/pancreatic-carcinosarcoma-with-rare-long-term-survival-case-report-and-review-of-the-literature
#10
REVIEW
Zhe Jia, Ke Zhang, RongHai Huang, XinGang Zhou, Li Jiang
PATIENT CONCERNS: We report a rare case of pancreatic carcinosarcoma involving a 44-year-old woman. The patient complained of discomfort associated with the upper abdomen and jaundice of skin and sclera for 1 week. DIAGNOSES: After hospitalization, relevant examinations were completed. The disease was diagnosed as carcinoma of the pancreatic head. INTERVENTIONS: Whipple procedure was conducted in May 2013. Intraoperative exploration indicated 2 components of the tumor: a fish-shaped gray matter and a hard structure similar to cancellous bone...
January 2017: Medicine (Baltimore)
https://www.readbyqxmd.com/read/28032528/chemotherapy-rechallenge-after-regorafenib-treatment-in-metastatic-colorectal-cancer-still-hope-after-the-last-hope
#11
Paola Bertocchi, Francesca Aroldi, Tiziana Prochilo, Fausto Meriggi, Giordano Domenico Beretta, Alberto Zaniboni
INTRODUCTION: The introduction of biological agents in cancer therapy is changing the progression of metastatic colorectal cancer. Currently, resistance to biological agents is an emerging problem; the progression of the disease is caused by the development of resistant clones. According to some authors, these clones can be re-sensitized to traditional and previously utilized chemotherapy agents. The results of the CORRECT study demonstrated the efficacy of regorafenib monotherapy in both KRAS wild type and mutant pretreated patients (pts)...
April 2017: Journal of Chemotherapy
https://www.readbyqxmd.com/read/27936107/structural-analysis-of-thymidylate-synthase-from-kaposi-s-sarcoma-associated-herpesvirus-with-the-anticancer-drug-raltitrexed
#12
Yong Mi Choi, Hyun Ku Yeo, Young Woo Park, Jae Young Lee
Kaposi's sarcoma-associated herpesvirus (KSHV) is a highly infectious human herpesvirus that causes Kaposi's sarcoma. KSHV encodes functional thymidylate synthase, which is a target for anticancer drugs such as raltitrexed or 5-fluorouracil. Thymidylate synthase catalyzes the conversion of 2'-deoxyuridine-5'-monophosphate (dUMP) to thymidine-5'-monophosphate (dTMP) using 5,10-methylenetetrahydrofolate (mTHF) as a co-substrate. The crystal structures of thymidylate synthase from KSHV (apo), complexes with dUMP (binary), and complexes with both dUMP and raltitrexed (ternary) were determined at 1...
2016: PloS One
https://www.readbyqxmd.com/read/27703008/the-role-of-folate-transport-in-antifolate-drug-action-in-trypanosoma-brucei
#13
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
#14
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
#15
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
#16
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
#17
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
#18
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
#19
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
#20
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
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