1,721,903 research outputs found
Development of new promising antimetabolite, DFP-11207 with self-controlled toxicity in rodents
No full textMasakazu Fukushima, Kenzo Iizuka, Cheng Jin, Chun Zhang, Mei Hong, Kiyoshi Eshima Division of Oncology Research and Development, Delta-Fly Pharma Inc., Kawauchi-cho, Tokushima, Japan Abstract: To reduce 5-fluorouracil (5-FU)-induced serious toxicities without loss of antitumor activity, we have developed DFP-11207, a novel fluoropyrimidine, which consists of 1-ethoxymethyl-5-fluorouracil (EM-FU; a precursor form of 5-FU), 5-chloro-2,4-dihydroxypyridine (CDHP; an inhibitor of 5-FU degradation), and citrazinic acid (CTA; an inhibitor of 5-FU phosphorylation). In vitro studies of DFP-11207 indicated that it strongly inhibited the degradation of 5-FU by dihydropyrimidine dehydrogenase (DPD) in homogenates of the rat liver, and also inhibited the phosphorylation of 5-FU by orotate phosphoribosyltransferase (OPRT) in tumor tissues in a similar magnitude of potency by CDHP and CTA, respectively. Especially, DFP-11207 inhibited the intracellular phosphorylation of 5-FU in tumor cells in a dose-dependent manner whereas CTA alone did not protect intracellular 5-FU phosphorylation. These results postulate that DFP-11207 rapidly entered into the cell and the free CTA produced from DFP-11207 inhibited the phosphorylation of 5-FU in the cell. Furthermore, following oral administration of DFP-11207, CTA was found to be highly retained in the gastrointestinal (GI) tract compared to other tissues in rats. Interestingly, EM-FU, the prodrug of 5-FU was found to specifically produce 5-FU by various species of liver microsomes. When DFP-11207 was administered to rats, the plasma level of 5-FU was persisted for a long-time with lower Cmax and longer half-life than that from other 5-FU prodrugs. The antitumor activity of DFP-11207 was evaluated in human tumor xenografts in nude rats and found that DFP-11207 showed an antitumor activity in a dose-dependent fashion and its efficacy is equivalent to reference 5-FU drugs. In striking contrast, DFP-11207 manifested no or less 5-FU-related toxicities, such as a decrease in body weights, GI injury, and myelosuppression, especially thrombocytopenia. Taken together, the preclinical evaluation of DFP-11207 strongly indicates that DFP-11207 be a potential new version of the oral fluoropyrimidine prodrug for further clinical development. Keywords: antimetabolite, 5-FU, citrazinic acid, 5-chloro-2,4-dihydroxypyridine, antitumor activity, myelo-toxicit
Demographics by child weight status (N = 11207).
No full textDemographics by child weight status (N = 11207).</p
Adjusted and unadjusted differences in mean CBCL scores comparing overweight/obese and normal weight children (N = 11207).
No full textAdjusted and unadjusted differences in mean CBCL scores comparing overweight/obese and normal weight children (N = 11207).</p
Abstract 5099: Development of novel antimetabolite, DFP-11207, with self-toxicity protection and its promising preclinical and clinical profiles
No full textAbstract
Background: For over 50 years, 5-fluorouracil (5-FU) has played a critical role in the systemic chemotherapy of various gastrointestinal cancers including gastric, colorectal and pancreatic cancer which are the leading causes of cancer death globally. Although systemic cytotoxics such as 5-FU can modestly prolong overall survival in the adjuvant and advanced settings, but at the cost of unpleasant toxicities. Therefore better drug formulations are desirable.
Methods: To this end, we developed a new conceptual fluoropyrimidine, DFP-11207 that is engineered to reduce toxicity without loss of antitumor activity as well in addition to providing sustained concentrations of the active anticancer moiety. DFP-11207 contains three components in one formulation: 1-ethoxymethyl-5-fluorouracil (EM-FU) as a prodrug of 5-FU, 5-chloro-2,4-dihyroxypyridine (CDHP) as a potent inhibitor of 5-FU degradation and cytrazinic acid (CTA) as a gastrointestinal regulator of 5-FU phosphorylation.
Results: In in vitro metabolism studies using cell-free extracts from plasma, liver and tumors or intact tumor cells, DFP-11207 was rapidly hydrolyzed to 3 components and subsequently EM-FU was specifically converted to 5-FU by liver microsomes, and CDHP and CTA strongly inhibited 5-FU degradation and phosphorylation, respectively. Following consecutive oral administration to human tumor-bearing nude rats, DFP-11207 attained favorable antitumor efficacy and long-sustained PK profiles with lack of GI- and myelo-toxicities. Next, in investigational clinical study in patients with solid tumors, 12 patients were treated at 8 unique dose levels of DFP-11207, ranging from 40 to 440mg/m2/day by each 1 pt. MTD and RD of daily and 28-day consecutive DFP-11207 was found to be 440 (n=2) and 330 mg/m2 (n=6), respectively. The main AEs were nausea,, anemia, neutropenia, febrile neutropenia but these events were very mild, and no thrombocytopenia was observed as expected. Furthermore, review of the preliminary PK data, DFP-11207 at 330 mg/m2 resulted in a desirable low but efficacious (~15- 30 ng/ml) steady-state plasma concentration of 5-FU. Interestingly, some of patients heavily treated with therapeutic drugs had a stable-disease for long periods.
Conclusion: Our preclinical and early clinical data with DFP-11207 suggest that it’s a promising compound for the treatment of gastrointestinal cancers and can overcome the shortcomings of all other oral fluoropyrimidines.
Citation Format: Masakazu Fukushima, Kenzo Iizuka, Kokoro Eshima, Chung Zhang, Cheng Jin, Kiyoshi Eshima, Jaffer Ajani. Development of novel antimetabolite, DFP-11207, with self-toxicity protection and its promising preclinical and clinical profiles [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5099. doi:10.1158/1538-7445.AM2017-5099</jats:p
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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