Cytopenia induction by 5-fluorouracil identifies thrombopoietic mutants in sensitized ENU mutagenesis screens

Anderson, Nicole; Berberovic, Zorana; Berndl, Elizabeth; Bailey, Monica L.; Flenniken, Ann M.; Osborne, Lucy R.; Adamson, S. Lee; Rossant, Janet; Wang, Chen; Minden, Mark D.; McNagny, Kelly M.; Paulson, Robert F.; Barber, Dwayne L.; Stanford, William L.

doi:10.1016/j.exphem.2011.09.007

Cited by 7 publications

(6 citation statements)

References 21 publications

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“…It has been reported that, 11 days after 5-FU treatment, young platelets in mouse blood display larger microtubule coils than untreated platelets [31]. An increased population of mature MKs appears after 7 days in 5-FU-treated mice, compared to 14 days in untreated mice [32]. We suspected that circulating proplatelets generated in vivo from an increased population of mature MKs would be detectable 7 days after 5-FU treatment.…”

Section: Discussionmentioning

confidence: 87%

Terminal Platelet Production is Regulated by Von Willebrand Factor

et al. 2013

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It is established that proplatelets are formed from mature megakaryocytes (MK) as intermediates before platelet production. Recently, the presence of proplatelets was described in blood incubated in static conditions. We have previously demonstrated that platelet and proplatelet formation is upregulated by MK exposure to high shear rates (1800 s−1) on immobilized von Willebrand factor (VWF). The purpose of the present study was to investigate whether VWF is involved in the regulation of terminal platelet production in blood. To this end, Vwf −/− mice, a model of severe von Willebrand disease, were used to create a situation in which blood cells circulate in a vascular tree that is completely devoid of VWF. Murine platelets were isolated from Vwf −/− and Vwf +/+ blood, exposed to VWF at 1800 s−1 in a microfluidic platform, and examined by means of videomicroscopy, as well as fluorescence and activation studies. Proplatelets became visible within 5 minutes, representing 38% of all platelets after 12 minutes and 46% after 28 min. The proportion of proplatelets was 1.8-fold higher in blood from Vwf−/− mice than from Vwf+/+ mice, suggesting a role of VWF in vivo. Fragmentation of these proplatelets into smaller discoid platelets was also observed in real-time. Platelets remained fully activatable by thrombin. Compensation of plasmatic VWF following hydrodynamic gene transfer in Vwf−/− mice reduced the percentage of proplatelets to wild-type levels. A thrombocytopenic mouse model was studied in the flow system, 7 days after a single 5-FU injection. Compared to untreated mouse blood, a 2-fold increase in the percentage of proplatelets was detected following exposure to 1800 s−1 on VWF of samples from mice treated with 5-FU. In conclusion, VWF and shear stress together appear to upregulate proplatelet reorganization and platelet formation. This suggests a new function for VWF in vivo as regulator of bloodstream thrombopoiesis.

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Section: Discussionmentioning

confidence: 87%

Terminal Platelet Production is Regulated by Von Willebrand Factor

et al. 2013

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“…Heavy ion mutagenesis is a new physical mutagenesis technique with high bioavailability, high energy density, poor repair effects and good spatial resolution of energy deposition compared with traditional radiation sources (e.g., UV, γ- and χ-rays); thus, it can produce more extensive mutation [ 11 – 13 ]. As a chemical mutagenesis method, 5-fluorouracil (5-FU) is a structural analog of uracil that inhibits the synthesis of DNA and some RNA [ 14 , 15 ], and it has been successfully used for microbial mutagenesis and cancer treatment as an effective chemical mutagen [ 16 , 17 ] .…”

Section: Introductionmentioning

confidence: 99%

Heavy ion mutagenesis combined with triclosan screening provides a new strategy for improving the arachidonic acid yield in Mortierella alpina

Zhang

Dong

et al. 2018

BMC Biotechnol

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BackgroundArachidonic acid (ARA), which is a ω-6 polyunsaturated fatty acid, has a wide range of biological activities and is an essential component of cellular membranes in some human tissues. Mortierella alpina is the best strain for industrial production of ARA. To increase its yield of arachidonic acid, heavy ion beam irradiation mutagenesis of Mortierella alpina was carried out in combination with triclosan and octyl gallate treatment.ResultsThe obtained mutant strain F-23 ultimately achieved an ARA yield of 5.26 g L− 1, which is 3.24 times higher than that of the wild-type strain. In addition, quantitative real-time PCR confirmed that the expression levels of fatty acid synthase (FAS), Δ5-desaturase, Δ6-desaturase, and Δ9-desaturase were all significantly up-regulated in the mutant F-23 strain, especially Δ6- and Δ9-desaturase, which were up-regulated 3- and 2-fold, respectively.ConclusionsThis study confirmed a feasible mutagenesis breeding strategy for improving ARA production and provided a mutant of Mortierella alpina with high ARA yield.

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“…With respect to the effects of soluble 5-FU, this study agreed with separate reports using BALB/C mice demonstrating that the nadir of blood counts occurred a week after a single dose of 120 mg/kg IP 5-FU. [25–27] When delivered in solution form, 5-FU significantly reduced lymphocyte counts (Figure 5E) and granulocyte counts (Figure 5F) within the first week of treatment compared to untreated mice (p < 0.05) while there were no significant differences in lymphocyte nor granulocyte counts between mice treated with 5-FU-loaded PLGA pellets and mice receiving no treatment (Figures 5E & 5F). However, there was an observed trend toward the 5-FU-loaded pellets being cytotoxic with respect to lymphocytes and granulocytes.…”

Section: Resultsmentioning

confidence: 99%

Antitumor Efficacy and Toxicity of 5-Fluorouracil-Loaded Poly(Lactide Co-glycolide) Pellets

Leelakanok

Geary

Salem

2018

Journal of Pharmaceutical Sciences

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The aim of this study was to formulate a biodegradable implant capable of imparting local antitumor activity through the sustained release of the chemotherapeutic agent, 5-fluorouracil (5-FU). Thus, injectable pellets (<1.2 mm diameter) made from poly(lactide co-glycolide) (PLGA) and loaded with 5-FU at varying drug:polymer ratios were fabricated using hot-melt extrusion and tested for their ability to provide sustained release of 5-FU in in vitro and in vivo settings. In addition, these formulations were compared against soluble 5-FU for their antitumor activity in vivo as well as for their toxicity. It was demonstrated that the release rate of 5-FU from PLGA pellets was directly related to the percentage of 5-FU in the pellets. PLGA pellets loaded with 50% w/w 5-FU exhibited comparable, and significantly enhanced, antitumor activity (as measured by tumor volumes and survival) in vivo in a thymoma and colon cancer model, respectively, when compared to an equivalent bolus dose (120 mg/kg) of soluble 5-FU. We concluded that 5-FU-loaded PLGA pellets were more effective and specifically less erythrotoxic than 5-FU bolus injections and therefore may prove to be of benefit as an intraoperative adjunct therapy for patients with cancers that are sensitive to 5-FU and who are undergoing tumor resection.

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Cytopenia induction by 5-fluorouracil identifies thrombopoietic mutants in sensitized ENU mutagenesis screens

Cited by 7 publications

References 21 publications

Terminal Platelet Production is Regulated by Von Willebrand Factor

Terminal Platelet Production is Regulated by Von Willebrand Factor

Heavy ion mutagenesis combined with triclosan screening provides a new strategy for improving the arachidonic acid yield in Mortierella alpina

Antitumor Efficacy and Toxicity of 5-Fluorouracil-Loaded Poly(Lactide Co-glycolide) Pellets

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