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Emerson Y Chen, Charles D Blanke, Daniel G Haller, Al B Benson, Tomislav Dragovich, Heinz-Josef Lenz, Carlos Robles, Hong Li, Motomi Mori, Nora Mattek, Rachel E Sanborn, Charles D Lopez
OBJECTIVE: Colorectal cancer (CRC) is the second leading cause of cancer death in the United States. Cyclooxygenase-2 (COX-2) overexpression is associated with increased tumor invasiveness and proliferation in CRC, and COX-2 inhibition has demonstrated chemopreventive activity. This study investigated the addition of celecoxib, a selective COX-2 inhibitor, to the irinotecan, 5-fluorouracil, and leucovorin (IFL) regimen for patients with previously untreated metastatic CRC. PATIENTS AND METHODS: Forty-seven patients enrolled in this single-arm phase II study received celecoxib at 400 mg orally twice daily in combination with weekly irinotecan (125 mg/m), 5-fluorouracil (500 mg/m), and leucovorin (20 mg/m) for 4 weeks every 6 weeks...
May 18, 2018: American Journal of Clinical Oncology
Harry Yoon, Anita Choudhary, Ramla Kosozi, Gurvinder Singh Bali, Ali Zaidi, Ajlan Atasoy, Arlene A Forastiere, Michael K Gibson
LESSON LEARNED: Panitumumab plus irinotecan is not active for the treatment of esophageal adenocarcinoma. BACKGROUND: Esophageal adenocarcinoma (EAC) is a lethal cancer with increasing incidence. Panitumumab (Pa) is a fully humanized IgG2 monoclonal antibody against human EGFR. Cetuximab (Cx) combined with irinotecan (Ir) is active for second-line treatment of colorectal cancer. This phase II study was designed to evaluate Pa plus Ir as second-line therapy for advanced EAC...
May 16, 2018: Oncologist
Akihiro Ohmoto, Masami Suzuki, Erina Takai, Hirofumi Rokutan, Yuko Fujiwara, Chigusa Morizane, Kazuyoshi Yanagihara, Tatsuhiro Shibata, Shinichi Yachida
Gastroenteropancreatic neuroendocrine carcinoma (GEP-NEC) is a rare and devastating malignancy, and preclinical studies are needed to evaluate potential therapeutic regimens. Here, we examined the antitumor effects of cisplatin (CDDP), etoposide (ETP) and irinotecan (CPT-11) and their combinations on GEP-NEC using three small-cell GEP-NEC cell lines (pancreatic NEC, A99; esophageal NEC, TYUC-1; duodenum NEC, TCC-NECT-2). In vitro studies were conducted using cell viability assays. In vivo experiments were conducted in mice inoculated with A99 or TCC-NECT-2 and treated with no agent, CDDP, CDDP+ETP (EP) or CDDP+CPT-11 (IP)...
April 20, 2018: Oncotarget
Maria Rosaria di Nunzio, Yasmin Douhal, Juan Angel Organero, Abderrazzak Douhal
This work reports on photophysical studies of the irinotecan (IRT) anti-cancer drug in water solutions of different acidities (pH = 1.11-9.46). We found that IRT co-exists as mono-cationic (C1), di-cationic (C2), or neutral (N) forms. The population of each prototropic species depends on the pH of the solution. At pH = 1.11-3.01, the C1 and C2 structures are stabilized. At pH = 7.00, the most populated species is C1, while at pH values larger than 9.46 the N form is the most stable species. In the 1.11-2.61 pH range, the C1* emission is efficiently quenched by protons to give rise to the emission from C2*...
May 15, 2018: Physical Chemistry Chemical Physics: PCCP
Qiong Yang, Yuanyuan Huang, Zhimin Jiang, Huizhong Wang, Weiyu Li, Bei Zhang, Derong Xie
Purpose: The third- or later-line therapy available often yield poor survival benefit in patients metastatic colorectal cancer (mCRC). The retrospective study aimed to evaluate efficacy of rechallenge of oxaliplatin-containing regimens. Patients and methods: Patients with mCRC who progressed from fluoropyrimidine, oxaliplatin, and irinotecan in the first- and second-line chemotherapy, were treated by reexposure to oxaliplatin-containing regimen. Patients treated by anti-epidermal growth factor receptor (EGFR) antibodies with irinotecan were included in the control arm...
2018: OncoTargets and Therapy
Danuta Jantas, Beata Grygier, Justyna Zatorska, Władysław Lasoń
The participation of group III metabotropic glutamate receptors (mGluRs) in cancer growth and progression is still an understudied issue. Based on our recent data on high expression of mGluR8 in human neuroblastoma SH-SY5Y cells, in the present study we evaluated the effect of an mGluR8-specific positive allosteric modulator (PAM: AZ12216052) and orthosteric agonist ((S)-3,4-DCPG) on chemotherapeutic (doxorubicin, irinotecan or cisplatin)-evoked cell damage in undifferentiated (UN-) and retinoic acid-differentiated (RA-) SH-SY5Y cells...
May 12, 2018: Basic & Clinical Pharmacology & Toxicology
Satya Das, Kristen K Ciombor, Sigurdis Haraldsdottir, Richard M Goldberg
Choosing the optimal treatment approach for patients with metastatic colorectal cancer (mCRC) demands that oncologists assess both clinical and genomic variables and individualize care based upon the findings. Clinically, choices depend on assessing the side of the colon in which the primary tumor originates, the sites and burden of metastatic disease, the patient's performance status, and their individual comorbidities. Genomic assessment of the tumor to discern the mutational status of genes such as RAS/RAF, HER2, and TRK, as well as assessing whether tumors have defective mismatch repair (dMMR) or high microsatellite instability (MSI-H), all factor in to potential treatment options and can determine clinical trial eligibility...
May 11, 2018: Current Treatment Options in Oncology
Laetitia Marzi, Keli Agama, Junko Murai, Simone Difilippantonio, Amy James, Cody J Peer, William D Figg, Daniel Beck, Mohamed S A Elsayed, Mark Cushman, Yves Pommier
Contrary to other anticancer targets, topoisomerase I (TOP1) is targeted by only one chemical class of FDA-approved drugs: topotecan and irinotecan, the derivatives of the plant alkaloid, camptothecin. The indenoisoquinolines LMP400, LMP744 and LMP776 are novel non-camptothecin TOP1 inhibitors in clinical trial, which overcome the limitations of camptothecins. To further improve metabolic stability, their methoxy groups have been replaced by a fluorine, as in the fluoroindenoisoquinolines NSC 781517 (LMP517), NSC 779135 (LMP135) and NSC 779134 (LMP134)...
May 10, 2018: Molecular Cancer Therapeutics
Julia Martinez-Perez, M Carmen Riesco-Martinez, Rocio Garcia-Carbonero
TAS102 is an oral thymidine-based nucleoside analogue that has been approved for the treatment of patients with metastatic colorectal cancer (mCRC) previously treated with, or not candidates for, available therapies including fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapies, anti-vascular endothelial growth factor (VEGF) agents and, if RAS wild-type, anti-epidermal growth factor receptor (EGFR) therapy. The pivotal RECOURSE phase III trial demonstrated a significant improvement in disease control rate, progression-free (PFS) and overall survival (OS) as compared with placebo in patients with refractory mCRC...
May 10, 2018: Expert Opinion on Drug Safety
Rebecca Wellmann, Brittany A Borden, Keith Danahey, Rita Nanda, Blase N Polite, Walter M Stadler, Mark J Ratain, Peter H O'Donnell
BACKGROUND: Germline and tumor pharmacogenomics impact drug responses, but germline markers less commonly guide oncology prescribing. The authors hypothesized that a critical number of clinically actionable germline pharmacogenomic associations exist, representing clinical implementation opportunities. METHODS: In total, 125 oncology drugs were analyzed for positive germline pharmacogenomic associations in journals with impact factors ≥5. Studies were assessed for design and genotyping quality, clinically relevant outcomes, statistical rigor, and evidence of drug-gene effects...
May 9, 2018: Cancer
Shweta Lawania, Siddharth Sharma, Navneet Singh, Digamber Behera
AIM: To evaluate the association of three XPF polymorphic variants (673 C>T, 11985 A>G, G415A) with lung cancer, overall survival and clinical response in North Indians. METHODS: Genotyping was performed using PCR-restriction fragment length polymorphism. RESULTS: A total of 673 C>T polymorphism was associated with 1.5-fold increased lung cancer risk for heterozygous genotype (CT; p = 0.03). Adenocarcinoma patients with 673 C>T polymorphism carrying heterozygous genotype (CT) had a lower hazard ratio (p = 0...
May 9, 2018: Future Oncology
Amanda Townsend, Niall C Tebbutt, Christos S Karapetis, Pamela Cooper, Nimit Singhal, Sue J Yeend, Louise Pirc, Rohit Joshi, Jennifer Elizabeth Hardingham, Timothy Price
PURPOSE: Inhibition of mTOR in addition to EGFR may overcome resistance to EGFR inhibitors in metastatic colorectal cancer (mCRC). This phase Ib/II study evaluated the safety and efficacy of the combination of irinotecan, panitumumab and everolimus. EXPERIMENTAL DESIGN: Patients with KRAS exon 2 WT mCRC following failure of fluoropyrimidine based therapy received IV irinotecan and panitumumab every 2 weeks, and everolimus orally throughout a 14 day cycle. The primary endpoint of the phase II study was response rate (RR)...
May 8, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Nasha Qiu, Jianqing Gao, Qi Liu, Jinqiang Wang, Youqing Shen
Gene therapy has demonstrated effectiveness in many genetic diseases as evidenced by recent clinical applications. Viral vectors have been extensively tested in clinical gene-therapy trials, but nonviral vectors such as cationic polymers or lipids are much less used due to their lower gene-transfection efficiencies. However, the advantages of nonviral vectors, such as easily tailored structures, nonimmunogenetics, and relatively low cost, still drive great efforts to improve their transfection efficiencies...
May 8, 2018: Biomacromolecules
Qianqian Yu, Tao Zhang, Conghua Xie, Hong Qiu, Bo Liu, Liu Huang, Ping Peng, Jueping Feng, Jigui Chen, Aihua Zang, Xianglin Yuan
PURPOSE: To investigate the association between UDP-glucuronosyltransferase (UGT)1A polymorphisms and irinotecan-treatment efficacy in a Chinese population with metastatic colorectal cancer (mCRC). METHODS: The present study was based on a prospective multicenter trial of Chinese mCRC patients treated with irinotecan-based chemotherapy (NCT01282658, registered at ). Fifteen single-nucleotide polymorphisms (SNPs) in four UGT1A genes were selected for genotyping in 164 patients...
May 4, 2018: Cancer Chemotherapy and Pharmacology
L Chauchat, C Tanguay, N J Caron, S Gagné, F Labrèche, J F Bussières
Purpose The aim of this study was to monitor environmental contamination by 10 antineoplastic drugs in Canadian oncology pharmacy and patient care areas. The secondary objective was to explore the impact of factors that may explain contamination. Methods Twelve standardized sites were sampled in each center (six in the pharmacy and six in patient care areas). Each sample was prepared to allow quantification of seven antineoplastic drugs (cyclophosphamide, ifosfamide, methotrexate, cytarabine, gemcitabine, 5-fluorouracil, irinotecan) by UPLC-MS-MS...
January 1, 2018: Journal of Oncology Pharmacy Practice
Arthur Lui, Karen Mulder, Christine Brezden-Masley, Michael Vickers, Jose Monzon, Hagen Kennecke, Rakesh Goel, Larissa Vos, Sunita Ghosh, Horia Marginean, Anthony Fields, Jean Maroun, Jennifer Spratlin
Purpose Chemotherapy remains the primary treatment for metastatic gastric/GEJ cancer but optimal agents and schedule remain controversial. This study examined the safety and efficacy of first-line Irinotecan, capecitabine (Xeloda®), and Oxaliplatin (IXO). Patients and Methods Eligible patients with HER2-unamplified/unknown, metastatic gastric/GEJ adenocarcinoma were treated with 21-day cycle IXO at dose level 1 (DL1: Day 1 O-100 mg/m2 & I-160 mg/m2 IV, Day 2-15 X-1900 mg/m2 /day PO divided doses) or modified IXO (mIXO): Day 1 O-85 mg/m2 & I-120 mg/m2 IV, Day 2-15 X-1425 mg/m2 /day PO divided doses)...
May 4, 2018: Investigational New Drugs
Osman Ciftci, Nese Basak Turkmen, Asli Taslıdere
Irinotecan (CPT-11), commonly used in the treatment of many cancer types, may have several side effects that limit the use of CPT-11 in specific tissues such as the heart. In the current study, positive effects of curcumin (CRC) was determined in terms of antioxidant and anti-inflammatory properties against heart damage, caused by CPT-11, in rats. Rats were divided randomly into four equal groups (Control, CPT-11, CRC, and CPT-11 + CRC). CPT-11 10 mg/kg/day was administered intraperitoneally and CRC 100 mg/kg-1 was given orally...
May 2, 2018: Naunyn-Schmiedeberg's Archives of Pharmacology
Hironaga Satake, Yu Sunakawa, Yuji Miyamoto, Masato Nakamura, Hiroshi Nakayama, Manabu Shiozawa, Akitaka Makiyama, Kazuma Kobayashi, Yutaro Kubota, Misuzu Mori, Masahito Kotaka, Akinori Takagane, Masahiro Gotoh, Masahiro Takeuchi, Masashi Fujii, Wararu Ichikawa, Takashi Sekikawa
FOLFOXIRI plus bevacizumab is considered a standard initial therapy for metastatic colorectal cancer (mCRC). However, few prospective trials have evaluated triplet therapy plus bevacizumab in patients with RAS mutant mCRC. Patients with an age of 20 to 75 years, and unresectable, measurable tumors harboring RAS mutation were given first-line treatment with bevacizumab (5 mg/kg on day 1) plus modified-FOLFOXIRI (irinotecan 150 mg/m2 , oxaliplatin 85 mg/m2 , levofolinate 200 mg/m2 , and fluorouracil 2400 mg/m2 as a 46-h continuous infusion on day 1, repeated every 2 weeks)...
April 10, 2018: Oncotarget
Akira Okita, Shin Takahashi, Kota Ouchi, Masahiro Inoue, Mika Watanabe, Mareyuki Endo, Hiroshi Honda, Yasuhide Yamada, Chikashi Ishioka
The consensus molecular subtypes (CMS) classification is one of the most robust colorectal cancer (CRC) classifications based on comprehensive gene expression profiles. This study aimed to clarify whether the CMS is a predictive factor for therapeutic effects of standard chemotherapies for metastatic CRC (mCRC). We retrospectively enrolled 193 patients with mCRCs, and using comprehensive gene expression data, classified them into 4 subtypes: CMS1-CMS4. The associations between the subtypes and treatment outcomes were analyzed...
April 10, 2018: Oncotarget
Pushkar Kulkarni, Marina Rajadurai, Aarti Sevilimedu, Surendar Basaveni, Swapna Yellanki, Raghavender Medishetti, Uday Saxena
Lung cancer is the single largest cause of cancer related deaths in the world. Current treatments include surgery, radiation therapy, chemotherapy using cytotoxic drugs, and monoclonal antibodies. Such treatments have limited efficacy due to diverse nature of lung cells involved and lack of tissue penetration. Cytotoxic drugs, while potent, have the enormous drawback of limited entry into the lung selectively, thus causing collateral damage to other tissues. To overcome these shortcomings, we report here the development of new magnetic irinotecan containing nanoparticles (NPs), which target the lung over other tissues by over 5-fold...
May 1, 2018: Drug Delivery and Translational Research
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