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Xiaolin Shen, Monika Mahajani, Jia Wang, Yaping Yang, Qipeng Yuan, Yajun Yan, Yuheng Lin
Acyl-CoAs are essential intermediates in the biosynthetic pathways of a number of industrially and pharmaceutically important molecules. When these pathways are reconstituted in a heterologous microbial host for metabolic engineering purposes, the acyl-CoAs may be subject to undesirable hydrolysis by the host's native thioesterases, resulting in a waste of cellular energy and decreased intermediate availability, thus impairing bioconversion efficiency. 4-hydroxycoumarin (4HC) is a direct synthetic precursor to the commonly used oral anticoagulants (e...
July 2017: Metabolic Engineering
Yechezkel Lande, Benjamin Fisch, Abraham Tsur, Jacob Farhi, Roni Prag-Rosenberg, Avi Ben-Haroush, Gania Kessler-Icekson, Muayad A Zahalka, Susan M Ludeman, Ronit Abir
How chemotherapy affects dormant ovarian primordial follicles is unclear. The 'burnout' theory, studied only in mice, suggests cyclophosphamide enhances primordial follicle activation. Using 4-hydroperoxycyclophosphamide (4hc) and phosphoramide mustard (PM), this study assessed how the active cyclophosphamide metabolites 4-hydroxycyclophosphamide (4-OHC) and PM, affect human primordial follicles. Frozen-thawed human ovarian samples were sliced and cultured with basic culture medium (cultured controls) or with 4hc/PM (3 µmol/l/10 µmol/l) (treated samples) for 24-48 h...
January 2017: Reproductive Biomedicine Online
Roman Poláček, Pavel Májek, Katarína Hroboňová, Jana Sádecká
At present, it is necessary to check the quality of many food products in which the content of coumarins is limited. Since a rapid and simple method for the determination of coumarin (COU), 4-hydroxycoumarin (4HC) and dicoumarol (DC) in tea samples was needed, we developed an alternative option to chromatography, i.e., fluorescence spectroscopy with multivariate calibration. The synchronous fluorescence spectra were recorded at constant wavelength differences 70, 80 and 90 nm from 200 to 400 nm. The different experimental parameters affecting the synchronous fluorescence intensities of the analytes were carefully studied and optimized...
March 2015: Journal of Fluorescence
N Pinto, E R Gamazon, N Antao, J Myers, A L Stark, A Konkashbaev, H K Im, S J Diskin, W B London, S M Ludeman, J M Maris, N J Cox, S L Cohn, M E Dolan
High-risk neuroblastoma is an aggressive malignancy, with high rates of treatment failure. We evaluated genetic variants associated with in vitro sensitivity to two derivatives of cyclophosphamide for association with clinical response in a separate replication cohort of neuroblastoma patients (n = 2,709). To determine sensitivity, lymphoblastoid cell lines (LCLs) were exposed to increasing concentrations of 4-hydroperoxycyclophosphamide (4HC; n = 422) and phosphoramide mustard (PM; n = 428). Genome-wide association studies were performed to identify single-nucleotide polymorphisms (SNPs) associated with sensitivity to 4HC and PM...
June 2014: Clinical Pharmacology and Therapeutics
Yuheng Lin, Xiaolin Shen, Qipeng Yuan, Yajun Yan
4-Hydroxycoumarin (4HC) type anticoagulants (for example, warfarin) are known to have a significant role in the treatment of thromboembolic diseases--a leading cause of patient morbidity and mortality worldwide. 4HC serves as an immediate precursor of these synthetic anticoagulants. Although 4HC was initially identified as a naturally occurring product, its biosynthesis has not been fully elucidated. Here we present the design, validation, in vitro diagnosis and optimization of an artificial biosynthetic mechanism leading to the microbial biosynthesis of 4HC...
2013: Nature Communications
A Rao, C Kuszynski, E Benner, P Iversen, J Jackson, M Bishop, S Joshi
Human chronic myelogenous leukemia (CML) is a unique malignancy in its cellular and molecular phenotypes. High dose therapy followed by stem cell transplantation seems to be one of the most effective treatment modalities for CML. However, allogeneic stem cell transplantation, a curative treatment modality, is limited due to the availability of matched siblings. On the other hand, the autologous stem cell harvests are contaminated with leukemic cells, and therefore a significant reduction of leukemic cells is desired before using the harvest for transplantation...
August 1997: International Journal of Oncology
Miyun Tsai-Turton, Brian T Luong, Youming Tan, Ulrike Luderer
The anticancer drug cyclophosphamide induces granulosa cell apoptosis and is detoxified by glutathione (GSH) conjugation. We previously showed that both cyclophosphamide treatment and GSH depletion induced granulosa cell apoptosis in rats, but the role of GSH in apoptosis in human ovarian cells has not been studied. Using the COV434 human granulosa cell line, we tested the hypotheses that (1) GSH depletion or treatment with 4-hydroperoxycyclophosphamide (4HC), a preactivated form of cyclophosphamide, induces apoptosis, (2) GSH depletion potentiates 4HC-induced apoptosis, and (3) 4HC-induced apoptosis is mediated by GSH depletion and oxidative stress...
July 2007: Toxicological Sciences: An Official Journal of the Society of Toxicology
I McNiece, C Civin, J Harrington, J Kellner, M Malehorn, J Turney, J Barber, R Jones
BACKGROUND: Multiple studies have demonstrated that 'purging' of autografts with 4-hydroperoxycyclophosphamide (4HC) or the related compound mafosfamide (Mf), to eradicate residual leukemia, produces the best results associated with autologous blood and marrow transplantation for AML. However, 4HC purging results in prolonged aplasia. Therefore, we evaluated the potential of ex vivo expansion of Mf-treated CD34+ cells from mobilized PBPC. METHODS: CD34+ cells were isolated from PBPC products and treated with 30 microg/mL Mf...
2006: Cytotherapy
Suzanne D Clutter, James E Fortney, Laura F Gibson
OBJECTIVE: Bone marrow stromal cell function is a critical influence on hematopoietic reconstitution following progenitor or stem cell transplantation. Stromal cells support hematopoietic cell migration, survival, and proliferation. We have previously reported that stromal cell matrix metalloproteinase-2 (MMP-2) is necessary for optimal support of pro-B-cell chemotaxis through its regulation of stromal cell-derived factor-1 (CXCL12) release. Following exposure to the topoisomerase II inhibitor, etoposide (VP-16), stromal cell MMP-2 protein expression is reduced...
November 2006: Experimental Hematology
Yoshihiro Hatta, Miki Takahashi, Yuko Enomoto, Noriaki Takahashi, Umihiko Sawada, Takashi Horie
We have previously reported that adenosine triphosphate (ATP) enhances the cytotoxic effects of 4-hydroperoxycyclophosphamide (4HC) on leukemia cells without affecting the normal hematopoietic stem cells. Increased cell membrane permeability induced by ATP may cause high incorporation of 4HC into leukemia cells, ultimately leading to cell death. In the present study, we show that ATP has cytotoxicity against PC14, a lung adenocarcinoma cell line. When PC14 cells were cultured with 1, 3, and 5 mM ATP, colony number significantly decreased to 91...
November 2004: Oncology Reports
Alberto D S Marques, Chhiu-Tsu Lin
Molecular complexes formed between a cooked food mutagen-carcinogen (2-amino-3-methylimidazo[4,5-f] quinoline, IQ) and a potent anti-mutagen (4-hydroxy-coumarin, 4HC) were synthesized and crystallized from a solution. The active functional groups in IQ and in 4HC that may involve in the formation of these complexes are investigated by UV-visible, infrared, and NMR spectroscopy. The geometrical conformations and heat of formation of IQ:4HC complexes were optimized by semi-empirical molecular orbital calculations...
May 27, 2004: Journal of Photochemistry and Photobiology. B, Biology
David A Rizzieri, Jeffrey T Talbot, Gwynn D Long, James J Vredenburgh, Christina Gasparetto, Clayton S Smith, Michael O Colvin, David Adams, Ashley Morris, Richard Dodge, Jennifer Loftis, Barbara Waters-Pick, Melissa Reese, Helen Carawan, Liang Piu Koh, Nelson J Chao
We have performed a phase I dose escalation of 4-Hydroperoxycyclophosphamide (4HC) purging of autologous peripheral blood progenitor cells (PBPCs) to improve the outcome of autologous transplantation for patients with myeloid leukemia. Peripheral blood stem cells were mobilized after cytosine arabinoside of 2 g/m(2) every 12 hours x 8 doses with etoposide of 40 mg/kg total dose infused over 4 days, followed by growth factor support. The preparative regimen included Busulfan of 1 mg/kg orally every 6 hours x 16 doses, followed by etoposide of 60 mg/kg x 1 day (the patient with chronic myeloid leukemia received cyclophosphamide of 60 mg/kg/d x 2 days in lieu of etoposide)...
March 2003: Biology of Blood and Marrow Transplantation
B Douglas Smith, Richard J Jones, Shing M Lee, Steve Piantadosi, Milada S Vala, Don Fuller, Steven D Gore, Steven J Noga, Paul V O'Donnell, Hayden Braine, Georgia B Vogelsang, Ephraim J Fuchs, Ian W Flinn, Robert A Brodsky, Richard F Ambinder, Carole B Miller
Between January 1987 and January 1997, 69 eligible patients with acute myeloid leukaemia (AML) in either second (CR2) or third (CR3) complete remission (CR2 = 60, CR3 = 9) underwent 4-hydroperoxycyclophosphamide-purged autologous bone marrow transplantation (BMT) at the Johns Hopkins Oncology Center. The patients' median age was 27 years (range 1-62) and all received busulphan and cyclophosphamide as their preparative regimen. The probability of event-free survival (EFS) at 5 years was 30% [95% Confidence Interval (CI): 19-42%] for CR2 patients and 22% (3-51%) for those in CR3, with a median follow up of 8 years in the surviving group...
June 2002: British Journal of Haematology
C B Miller, P A Rowlings, M J Zhang, R J Jones, S Piantadosi, A Keating, J O Armitage, S Calderwood, R E Harris, J P Klein, H M Lazarus, C A Linker, K A Sobocinski, D Weisdorf, M M Horowitz
BACKGROUND: Autologous bone marrow transplantation is an important therapy for patients with acute myelogenous leukemia (AML). However, leukemia in the graft may contribute to posttransplant relapse. Treatment of the graft with 4-hydroperoxycyclophosphamide (4HC) is sometimes used to decrease numbers of infused leukemia cells (4HC purging). No large controlled trials evaluating efficacy and toxicity of 4HC purging are reported. METHODS: We studied 294 patients reported to the Autologous Blood and Marrow Registry receiving either a 4HC-purged (n = 211) or unpurged (n = 83) autograft for AML in first (n = 209) or second (n = 85) remission...
November 2001: Experimental Hematology
R S Mehta, R Bornstein, I R Yu, R J Parker, C E McLaren, K P Nguyen, K T Li, J P Fruehauf
PURPOSE: To determine whether in vitro extreme drug resistance (EDR) assay results for patients with breast carcinoma were associated with clinical outcome after chemotherapy. PATIENTS AND METHODS: EDR assays were performed on tumor tissue obtained from 103 newly diagnosed breast cancer cases. EDR scores of 2 for low, 1 for intermediate, or 0 for extreme drug resistance were determined for each agent tested. In vitro EDR scores for 4-hydroxycyclophosphamide (4HC) and doxorubicin were summed for patients treated with AC, or for 4HC and 5-FU for patients treated with CMF...
April 2001: Breast Cancer Research and Treatment
S S Joshi, C A Kuszynski, E J Benner, M Bagchi, D Bagchi
Anticancer chemotherapeutic agents are effective in inhibiting growth of cancer cells in vitro and in vivo, however, toxicity to normal cells is a major problem. In this study, we assessed the effect of a novel IH636 grape seed proanthocyanidin extract (GSPE) to ameliorate chemotherapy-induced toxic effects in cultured Chang epithelial cells, established from nonmalignant human tissue. These cells were treated in vitro with idarubicin (Ida) (30 nM) or 4-hydroxyperoxycyclophosphamide (4HC) (1 microg/ml) with or without GSPE (25 microg/ml)...
1999: Antioxidants & Redox Signaling
N Takebe, S C Zhao, D Adhikari, S Mineishi, M Sadelain, J Hilton, M Colvin, D Banerjee, J R Bertino
The genetic transfer of drug resistance to hematopoietic cells is an attractive approach to overcoming myelosuppression caused by high-dose chemotherapy. Because cyclophosphamide (CTX) and methotrexate (MTX) are commonly used non-cross-resistant drugs, generation of dual drug resistance in hematopoietic cells that allows dose intensification may increase anti-tumor effects and circumvent the emergence of drug-resistant tumors. We constructed a retroviral vector containing both a human cytosolic ALDH-1 cDNA and a human doubly mutated DHFR cDNA (Phe22/Ser31; termed F/S in the description of constructs) to generate increased resistance to both CTX and MTX...
January 2001: Molecular Therapy: the Journal of the American Society of Gene Therapy
G Vogelsang, R Bitton, S Piantadosi, V Altomonte, T Horn, R Jones, C Miller, D Marcellus, R Abrams, A Hess
From March 1994 to November 1994, 16 patients with high risk hematological malignancies were entered in a phase I clinical trial, designed to confirm the toxicity of cyclosporine and gamma interferon given to induce autologous graft-versus-host disease (GVHD) after autologous bone marrow transplantation (ABMT). This trial was based on the results in a rodent model, in which cyclosporine given after ABMT induces an autoimmune syndrome (autologous GVHD) identical to allogeneic GVHD. Further, this autologous GVHD is associated with a graft-versus-tumor effect augmented by interferon that upregulates MHC class II expression on normal and tumor cells, the target of the cytolytic T cells in autologous GVHD...
September 1999: Bone Marrow Transplantation
L F Gibson, J Fortney, G Magro, S G Ericson, J P Lynch, K S Landreth
Optimizing chemotherapeutic drug delivery strategies relies, in part, on identification of the most clinically effective sequence, dose, and duration of drug exposure. The combination of dose intensive etoposide (VP-16) followed by cyclophosphamide has clinical efficacy in the treatment of advanced breast cancer. However, molecular mechanisms that underlie the effectiveness of this combination of chemotherapeutic agents have not been investigated. In this study we investigated regulation of BAX and BCL-2 expression by VP-16 and cyclophosphamide as a potential mechanism for the induction of breast cancer cell death induced by this regimen...
May 1999: Breast Cancer Research and Treatment
E Van Den Neste, F Bontemps, A Delacauw, S Cardoen, I Louviaux, J M Scheiff, E Gillis, P Leveugle, V Deneys, A Ferrant, G Van den Berghe
Because 2-chloro-2'-deoxyadenosine (CdA) is active in B-chronic lymphocytic leukemia (B-CLL), and may interfere with DNA repair, we investigated the potentiating effect of CdA on the cytotoxicity induced in vitro in B-CLL lymphocytes by cyclophosphamide (CP) derivatives, which induce DNA damage by DNA cross-linking. Exposure to CdA at clinically achievable concentrations for 2 h, followed by mafosfamide (MAF) or 4-hydroxycyclophosphamide (4HC) for 22 h, resulted in synergistic cytotoxicity in the majority of B-CLL samples tested...
June 1999: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
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