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Gemcitabine toxicity

Jiyan Mohammad, Harsharan Dhillon, Shireen Chikara, Sujan Mamidi, Avinash Sreedasyam, Kishore Chittem, Megan Orr, John C Wilkinson, Katie M Reindl
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers due to a late diagnosis and poor response to available treatments. There is a need to identify complementary treatment strategies that will enhance the efficacy and reduce the toxicity of currently used therapeutic approaches. We investigated the ability of a known ROS inducer, piperlongumine (PL), to complement the modest anti-cancer effects of the approved chemotherapeutic agent gemcitabine (GEM) in PDAC cells in vitro and in vivo . PDAC cells treated with PL + GEM showed reduced cell viability, clonogenic survival, and growth on Matrigel compared to control and individually-treated cells...
February 13, 2018: Oncotarget
Hiroshi Ishii, Natsumi Yamashita, Makoto Ueno, Shinichi Ohkawa, Akiko M Saito, Mitsugu Sekimoto
Introduction: In Japan, the age of patients with pancreatic cancer has increased. Combination chemotherapies such as 5-fluorouracil/leucovorin, oxaliplatin and irinotecan therapy and gemcitabine hydrochloride (GEM) +nab paclitaxel therapy have been developed as the standard treatments for young patients with advanced recurrent pancreatic cancer. However, both therapies produce toxicity and their administration is limited by the patients' age or performance status. The efficacy and safety data obtained in the GEST study-a large-scale randomised controlled study conducted in patients with pancreatic cancer in Japan-suggested that GEM +S-1 (GS) combination therapy is a promising candidate for those aged between 75 and 80 years...
2018: BMJ Open Gastroenterology
Jean Davidson, Zhewei Shen, Xue Gong, Jonathan R Pollack
While gemcitabine has been the mainstay therapy for advanced pancreatic cancer, newer combination regimens (e.g. FOLFIRINOX) have extended patient survival, though carry greater toxicity. Biomarkers are needed to better stratify patients for appropriate therapy. Previously, we reported that one-third of pancreatic cancers harbor deletions or deleterious mutations in key subunits of the SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeling complex. The SWI/SNF complex mobilizes nucleosomes on DNA, and plays a key role in modulating DNA transcription and repair...
February 9, 2018: Oncotarget
Yongchun Wang, Yongqiang Xu, Yinyuan Zheng, Ying Bao, Ping Wang
Objective: To determine the effect of postoperative hepatic arterial infusion chemotherapy (HAIC) on long-term survival of patients with pancreatic cancer (PC) after radical pancreatectomy. Methods: A total of 87 patients with PC underwent radical pancreatectomy in the First People's Hospital affiliated to Huzhou Normal College between June 2008 and May 2013. Among these patients, after surgery, 43 received two sessions of HAIC followed by four sessions of systemic chemotherapy (HAIC group), while 44 received six sessions of systemic chemotherapy alone (control group)...
2018: OncoTargets and Therapy
Suguru Yamada, Tsutomu Fujii, Yukihiro Yokoyama, Hiroki Kawashima, Osamu Maeda, Kojiro Suzuki, Tohru Okada, Eizaburo Ono, Junpei Yamaguchi, Nao Takano, Hideki Takami, Masamichi Hayashi, Yukiko Niwa, Yoshiki Hirooka, Yoshiyuki Ito, Shinji Naganawa, Yuichi Ando, Masato Nagino, Hidemi Goto, Yasuhiro Kodera
PURPOSE: For unresectable locally advanced (UR-LA) pancreatic cancer, chemoradiotherapy has been recommended by the NCCN guidelines. We designed a chemoradiotherapy protocol using nab-paclitaxel combined with gemcitabine (GnP) for patients with UR-LA pancreatic cancer. The purpose of this phase I study was to determine a recommended dose (RD) for this novel regimen. METHODS: Patients with UR-LA pancreatic cancer were eligible. The frequency of dose-limiting toxicities (DLTs) was evaluated, and the RD was determined...
March 3, 2018: Cancer Chemotherapy and Pharmacology
Christina Kratschmer, Matthew Levy
Pancreatic cancer is one of the most lethal malignancies. Treatment with the first-line agent, gemcitabine, is often unsuccessful because it, like other traditional chemotherapeutic agents, is non-specific, resulting in off-target effects that necessitate administration of subcurative doses. Alternatively, monomethyl auristatin E (MMAE) and monomethyl auristatin F (MMAF) are highly toxic small molecules that require ligand-targeted delivery. MMAE has already received FDA approval as a component of an anti-CD30 antibody-drug conjugate, brentuximab vedotin...
March 2, 2018: Molecular Therapy. Nucleic Acids
David E Gerber, Mark A Socinski, Joel W Neal, Heather A Wakelee, Keisuke Shirai, Lecia V Sequist, Rachel P Rosovsky, Rogerio C Lilenbaum, Bruno R Bastos, Chao Huang, Melissa L Johnson, Paul J Hesketh, Deepa S Subramaniam, Martin F Dietrich, Feng Chai, Yunxia Wang, Julia Kazakin, Brian Schwartz, Joan H Schiller, Julie R Brahmer, Ronan J Kelly
BACKGROUND: KRAS mutations are identified in approximately 25% of non-small cell lung cancer (NSCLC) cases and are associated with resistance to currently available targeted therapies. The MET oncogene may be implicated in malignant progression of KRAS-mutant tumors. In a pre-specified subset analysis of KRAS mutant cancers in an earlier phase 2 study of erlotinib plus the oral MET inhibitor tivantinib, combination therapy was associated with substantial clinical benefit compared to erlotinib alone (progression-free survival [PFS] HR 0...
March 2018: Lung Cancer: Journal of the International Association for the Study of Lung Cancer
Giovanni Schinzari, Ernesto Rossi, Francesco Pierconti, Giovanna Garufi, Santa Monterisi, Antonia Strippoli, Ettore D'Argento, Alessandra Cassano, Carlo Barone
Vinflunine is the only cytotoxic agent tested as a second line therapy in transitional cell carcinoma of the urothelium in a phase III trial. It is not largely employed in clinical practice because of the high incidence of grade 3-4 toxicity. We evaluated efficacy and safety of Vinflunine at the dose of 280 mg/m2 every 3 weeks associated with primary prophylaxis with granulocyte growth factors and laxatives for patients progressed after platinum + Gemcitabine. Overall survival was 8.5 months, progression-free survival 4...
February 2, 2018: Oncotarget
Zhibo Xie, Yifan Zhang, Chen Jin, Deliang Fu
This meta-analysis was designed to compare the efficacy and safety of gemcitabine-based regimens for the treatment advanced breast cancer (ABC). Altogether 15 studies involving 8195 ABC patients were retrieved for analysis. Compared with non-gemcitabine-based chemotherapies, patients receiving gemcitabine-based therapy exhibited better overall survival (OS), progression free survival (PFS), and objective response rate (ORR) (HR = 1.12, 95% CI 1.05 to 1.19; HR = 1.16, 95% CI 1.03 to 1.30; HR = 1.14, 95% CI 1...
January 23, 2018: Oncotarget
Maiyon Park, Danielle Upton, Melodie Blackmon, Valerie Dixon, Scott Craver, Dawn Neal, Derek Perkins
BACKGROUND: Pancreatic cancer is one of the leading causes of cancer related death and its incidence has risen steadily. Although anticancer drugs have been developed based on the new molecular findings, the drugs have produced unsatisfactory results due to toxicity and resistance. Thus, a complementary therapeutic intervention is urgently needed for pancreatic cancer patients. METHODS: The aim of this study was to assess the potential therapeutic effect of Anacardic acid on pancreatic cancer in vitro and elucidate its underlying mechanisms...
February 20, 2018: BMC Complementary and Alternative Medicine
Zefu Liu, Yunlin Ye, Xiangdong Li, Shengjie Guo, Lijuan Jiang, Pei Dong, Yonghong Li, Yanxia Shi, Weijun Fan, Yun Cao, Kai Yao, Zike Qin, Hui Han, Fangjian Zhou, Zhuowei Liu
PURPOSE: To investigate the effects of intra-arterial chemotherapy on T1 stage bladder cancer (Bca) and evaluate patient outcome with bladder-preserving treatment approaches. MATERIALS AND METHODS: A total of 238 patients with T1 stage Bca were retrospectively analyzed. Among them, 35 patients were categorized into the subgroup of highest-risk T1 stage according to the European Association of Urology guidelines and received immediate radical cystectomy (RC group), whereas 62 were classified as being highest-risk T1 patients but were unwilling to undergo RC and were treated with gemcitabine plus cisplatin intra-arterial chemotherapy (GC group)...
February 19, 2018: World Journal of Urology
Beata Hryciuk, Bartosz Szymanowski, Anna Romanowska, Ewa Salt, Bartosz Wasąg, Bartłomiej Grala, Jacek Jassem, Renata Duchnowska
Gemcitabine (GCB) is a pyrimidine antimetabolite widely used in various solid tumors as a single agent or as a component of multidrug regimens. In the majority of patients, GCB is well tolerated, however life-threatening complications occasionally occur. The current report presents four cases of severe acute toxicity, which included two that were fatal, following administration of GCB alone or in combination with cisplatin. Of the four cases, in one, a Naranjo Adverse Drug Reaction Probability Score was definite, in two, probable and in one possible...
February 2018: Oncology Letters
Ting Jin, Feng Jiang, Qi-Feng Jin, Yong-Feng Piao, Xiao-Zhong Chen
OBJECTIVE: A previous phase-2 trial to assess the addition of Endostar to gemcitabine and cisplatin (GC) chemotherapy showed that it improves prognosis in metastatic nasopharyngeal carcinoma (M-NPC) but the study cohort was small. We wished to update that phase-2 trial by enrolling an additional 44 patients and to assess the benefit of Endostar+GC chemotherapy. METHODS: An analysis of 72 M-NPC patients treated between July 2010 and November 2016 was done. The treatment regimen was a combination of gemcitabine (1,000 mg/m2) on days 1 and 8, cisplatin (80 mg/m2) on day 1, and Endostar (15 mg/day) from day 1 to day 14 of a 21-day cycle for ≥2 cycles...
January 31, 2018: Translational Oncology
Arndt Vogel, Stefan Kasper, Michael Bitzer, Andreas Block, Marianne Sinn, Henning Schulze-Bergkamen, Markus Moehler, Nicole Pfarr, Volker Endris, Benjamin Goeppert, Kirsten Merx, Elisabeth Schnoy, Jens T Siveke, Patrick Michl, Dirk Waldschmidt, Jan Kuhlmann, Michael Geissler, Christoph Kahl, Ralph Evenkamp, Torben Schmidt, Alexander Kuhlmann, Wilko Weichert, Stefan Kubicka
BACKGROUND: Combination chemotherapy has shown benefit in the treatment of biliary cancer and further improvements might be achieved by the addition of a biological agent. We report here the effect of chemotherapy with the monoclonal EGFR antibody panitumumab as therapy for KRAS wild-type biliary cancer. PATIENTS AND METHODS: Patients with advanced biliary tract cancer were randomised (2:1) to receive cisplatin 25 mg/m2 and gemcitabine 1000 mg/m2 on day 1 and day 8/q3w with (arm A) or without panitumumab (arm B; 9 mg/kg BW, i...
March 2018: European Journal of Cancer
T Ebata, S Hirano, M Konishi, K Uesaka, Y Tsuchiya, M Ohtsuka, Y Kaneoka, M Yamamoto, Y Ambo, Y Shimizu, F Ozawa, A Fukutomi, M Ando, Y Nimura, M Nagino
BACKGROUND: Although some retrospective studies have suggested the value of adjuvant therapy, no recommended standard exists in bile duct cancer. The aim of this study was to test the hypothesis that adjuvant gemcitabine chemotherapy would improve survival probability in resected bile duct cancer. METHODS: This was a randomized phase III trial. Patients with resected bile duct cancer were assigned randomly to gemcitabine and observation groups, which were balanced with respect to lymph node status, residual tumour status and tumour location...
February 2018: British Journal of Surgery
Stine Braendegaard Winther, Jon Kroll Bjerregaard, Katrine Rahbek Schonnemann, Mathilde Weisz Ejlsmark, Merete Krogh, Helle Anita Jensen, Per Pfeiffer
PURPOSE: Gemcitabine has been standard of care in advanced pancreatic adenocarcinomas (PC) for almost two decades. Randomized, primarily Japanese, studies have shown promising efficacy when combined with S-1 (GemS-1); however, no data are published in Caucasian patients. We report the first study with a combination of GemS-1 in an unselected cohort of Caucasian PC patients. METHODS: In this observational cohort study, we analyzed efficacy and toxicity prospectively...
January 31, 2018: Cancer Chemotherapy and Pharmacology
John Tat, Céline Loriot, Martha Henze, Charles Spruck, Brunhilde H Felding, Steven I Reed
The cyclin-dependent kinase-interacting proteins Cyclin-dependent Kinase Subunit 1 and 2 (CKS1 and 2) are frequently overexpressed in cancer and linked to increased aggressiveness and poor prognoses. We previously showed that CKS protein overexpression overrides the replication stress checkpoint activated by oncoproteins. Since CKS overexpression and oncoprotein activation/overexpression are often observed in the same tumors, we have hypothesized that CKS-mediated checkpoint override could enhance the ability of premalignant cells experiencing oncoprotein-induced replication stress to expand...
December 29, 2017: Oncotarget
Douglas R Vogus, Anusha Pusuluri, Renwei Chen, Samir Mitragotri
Combination chemotherapy is commonly used to treat late stage cancer; however, treatment is often limited by systemic toxicity. Optimizing drug ratio and schedule can improve drug combination activity and reduce dose to lower toxicity. Here, we identify gemcitabine (GEM) and doxorubicin (DOX) as a synergistic drug pair in vitro for the triple negative breast cancer cell line MDA-MB-231. Drug synergy and caspase activity were increased the most by exposing cells to GEM prior to DOX in vitro. While the combination was more effective than the single drugs at inhibiting MDA-MB-231 growth in vivo, the clear schedule dependence observed in vitro was not observed in vivo...
January 2018: Bioengineering & Translational Medicine
Clinton Yam, Rashmi K Murthy, Vicente Valero, Janio Szklaruk, Girish S Shroff, Carol J Stalzer, Aman U Buzdar, James L Murray, Wei Yang, Gabriel N Hortobagyi, Stacy L Moulder, Banu Arun
Background Tipifarnib is an orally active, competitive inhibitor of farnesyltransferase which has shown encouraging signs of activity either alone or when combined with other agents. Clinical studies of tipifarnib in combination with anti-estrogen therapy have yielded disappointing results. In contrast, tipifarnib appears to be synergistic in combination with anthracycline based chemotherapy. Here we report the results of the first prospective phase II trial evaluating the efficacy of the novel combination of tipifarnib and gemcitabine in the treatment of metastatic breast cancer...
January 27, 2018: Investigational New Drugs
Jacob E Shabason, Jerry Chen, Smith Apisarnthanarax, Nevena Damjanov, Bruce Giantonio, Arturo Loaiza-Bonilla, Peter J O'Dwyer, Mark O'Hara, Kim A Reiss, Ursina Teitelbaum, Paul Wissel, Jeffrey A Drebin, Charles Vollmer, Michael Kochman, Rosemarie Mick, Norge Vergara, Nirag Jhala, Abigail Doucette, John N Lukens, John P Plastaras, James M Metz, Edgar Ben-Josef
PURPOSE: Patients with locally advanced pancreatic cancer typically have poor outcomes, with a median survival of approximately 16 months. Novel methods to improve outcomes are needed. Nab-paclitaxel (Abraxane) has shown efficacy in pancreatic cancer and is FDA-approved for metastatic disease in combination with gemcitabine. Nab-paclitaxel is also a promising radiosensitizer based on laboratory studies, but it has never been clinically tested with definitive radiotherapy for locally advanced pancreatic carcinoma...
January 23, 2018: Cancer Chemotherapy and Pharmacology
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