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PloS One Jun 2010The number of promising therapeutic interventions for Duchenne Muscular Dystrophy (DMD) is increasing rapidly. One of the proposed strategies is to use drugs that are...
BACKGROUND
The number of promising therapeutic interventions for Duchenne Muscular Dystrophy (DMD) is increasing rapidly. One of the proposed strategies is to use drugs that are known to act by multiple different mechanisms including inducing of homologous fetal form of adult genes, for example utrophin in place of dystrophin.
METHODOLOGY/PRINCIPAL FINDINGS
In this study, we have treated mdx mice with arginine butyrate, prednisone, or a combination of arginine butyrate and prednisone for 6 months, beginning at 3 months of age, and have comprehensively evaluated the functional, biochemical, histological, and molecular effects of the treatments in this DMD model. Arginine butyrate treatment improved grip strength and decreased fibrosis in the gastrocnemius muscle, but did not produce significant improvement in muscle and cardiac histology, heart function, behavioral measurements, or serum creatine kinase levels. In contrast, 6 months of chronic continuous prednisone treatment resulted in deterioration in functional, histological, and biochemical measures. Arginine butyrate-treated mice gene expression profiling experiments revealed that several genes that control cell proliferation, growth and differentiation are differentially expressed consistent with its histone deacetylase inhibitory activity when compared to control (saline-treated) mdx mice. Prednisone and combination treated groups showed alterations in the expression of genes that control fibrosis, inflammation, myogenesis and atrophy.
CONCLUSIONS/SIGNIFICANCE
These data indicate that 6 months treatment with arginine butyrate can produce modest beneficial effects on dystrophic pathology in mdx mice by reducing fibrosis and promoting muscle function while chronic continuous treatment with prednisone showed deleterious effects to skeletal and cardiac muscle. Our results clearly indicate the usefulness of multiple assays systems to monitor both beneficial and toxic effects of drugs with broad range of in vivo activity.
Topics: Animals; Arginine; Behavior, Animal; Butyrates; Disease Models, Animal; Drug Therapy, Combination; Female; Gene Expression Profiling; Gene Expression Regulation; Heart; Mice; Mice, Inbred mdx; Muscles; Muscular Dystrophy, Duchenne; Prednisone; RNA, Messenger; Time Factors; Utrophin
PubMed: 20574530
DOI: 10.1371/journal.pone.0011220 -
Blood Mar 2007Malignancies associated with latent Epstein-Barr virus (EBV) are resistant to nucleoside-type antiviral agents because the viral enzyme target of these antiviral drugs,...
Malignancies associated with latent Epstein-Barr virus (EBV) are resistant to nucleoside-type antiviral agents because the viral enzyme target of these antiviral drugs, thymidine kinase (TK), is not expressed. Short-chain fatty acids, such as butyrate, induce EBV-TK expression in latently infected B cells. As butyrate has been shown to sensitize EBV(+) lymphoma cells in vitro to apoptosis induced by ganciclovir, arginine butyrate in combination with ganciclovir was administered in 15 patients with refractory EBV(+) lymphoid malignancies to evaluate the drug combination for toxicity, pharmacokinetics, and clinical responses. Ganciclovir was administered twice daily at standard doses, and arginine butyrate was administered by continuous infusion in an intrapatient dose escalation, from 500 mg/(kg/day) escalating to 2000 mg/(kg/day), as tolerated, for a 21-day cycle. The MTD for arginine butyrate in combination with ganciclovir was established as 1000 mg/(kg/day). Ten of 15 patients showed significant antitumor responses, with 4 CRs and 6 PRs within one treatment cycle. Complications from rapid tumor lysis occurred in 3 patients. Reversible somnolence or stupor occurred in 3 patients at arginine butyrate doses of greater than 1000 mg/(kg/day). The combination of arginine butyrate and ganciclovir was reasonably well-tolerated and appears to have significant biologic activity in vivo in EBV(+) lymphoid malignancies which are refractory to other regimens.
Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Arginine; Butyrates; Child; Child, Preschool; Drug Therapy, Combination; Epstein-Barr Virus Infections; Female; Ganciclovir; Humans; Lymphoma; Male; Middle Aged
PubMed: 17119113
DOI: 10.1182/blood-2006-01-024703 -
Blood Feb 2005Fetal hemoglobin (Hb F) levels increase in most patients with sickle cell disease following intermittent butyrate therapy. Although the full effects of butyrate on Hb F... (Clinical Trial)
Clinical Trial
Fetal hemoglobin (Hb F) levels increase in most patients with sickle cell disease following intermittent butyrate therapy. Although the full effects of butyrate on Hb F levels usually require multiple treatment cycles, in some patients a peak level is achieved after a few days of butyrate therapy. Our investigation of the mechanism(s) responsible for this rapid induction of Hb F by butyrate showed that reticulocyte gamma-globin chain synthesis markedly increased within 24 hours of butyrate exposure, without concomitant changes in reticulocyte gamma-globin mRNA levels. This suggests that butyrate might induce Hb F by increasing the efficiency of translation of gamma-globin mRNA. This hypothesis was confirmed by ribosome loading studies that demonstrated enrichment of the polysomal fraction of reticulocytes with gamma-globin mRNA following butyrate exposure. Thus, the induction of Hb F by butyrate may be mediated by translational effects in addition to its well-known effects on transcription of the gamma-globin genes.
Topics: Adult; Anemia, Sickle Cell; Arginine; Butyrates; Fetal Hemoglobin; Globins; Humans; Peptide Chain Initiation, Translational; Protein Biosynthesis; RNA, Messenger; Reticulocytes
PubMed: 15479724
DOI: 10.1182/blood-2004-02-0454 -
Cancer Immunology, Immunotherapy : CII Apr 2000Interleukin-2 (IL-2) and sodium butyrate allow rats to be cured of peritoneal carcinomatosis from colon cancer. We performed a phase I trial of IL-2 and high-dose... (Clinical Trial)
Clinical Trial
INTRODUCTION
Interleukin-2 (IL-2) and sodium butyrate allow rats to be cured of peritoneal carcinomatosis from colon cancer. We performed a phase I trial of IL-2 and high-dose arginine butyrate (ArgB) in patients with advanced metastatic colorectal cancer.
PATIENTS AND METHODS
From April to July 1997, six patients were included in the trail; they had a median age of 52 years, four had a performance status of 0, two had a performance status of 1 with normal biological functions. All patients had received at least two prior lines of chemotherapy. A fixed dose of 18 MIU/m2 IL-2,was administered by subcutaneous injection and ArgB was delivered via continuous intravenous infusion on days 1-6 with escalating doses starting at 2 g kg(-1) day(-1).
RESULTS
The planned dose escalation was not possible because of toxicities. A daily ArgB dose of 2 g/kg was delivered for nine cycles. Level 2 (4 g/kg) could not be delivered in three of the six patients because of liver toxicity. The dose-limiting toxicities were fatigue and liver function disturbances. The maximum tolerated dose for ArgB was 3 g kg(-1) day(-1), in combination with IL-2 at 12 MIU m2 day(-1). No clinical response was seen. Pharmacokinetic analysis showed large intra- and interindividual variations.
CONCLUSION
This schedule with a high dose of ArgB proved to be highly toxic with liver insufficiency. We will be running another trial with lower doses of ArgB calculated from the schedule used in the experimental model, starting at a dose of 20 mg kg(-1) day(-1) for ArgB and 200000 UI kg(-1) day(-1) IL-2, every 8 h.
Topics: Adjuvants, Immunologic; Aged; Animals; Arginine; Colorectal Neoplasms; Female; Humans; Infusions, Intravenous; Injections, Subcutaneous; Interleukin-2; Male; Middle Aged; Neoplasm Metastasis; Rats; Treatment Outcome
PubMed: 10782866
DOI: 10.1007/s002620050026 -
The Journal of Laboratory and Clinical... Dec 1998The exposure of endothelial cells to hypoxic environments regulates the expression of a number of genes with products that are vasoactive or mitogenic for vascular...
The exposure of endothelial cells to hypoxic environments regulates the expression of a number of genes with products that are vasoactive or mitogenic for vascular tissue, including platelet-derived growth factor, endothelin-1, and endothelial nitric oxide synthase. Hypoxia is also known to alter the adhesive properties of endothelium toward a variety of blood cell types. Thrombospondin-1 (TSP-1) is a glycoprotein with major roles in cellular adhesion and vascular smooth muscle proliferation and migration. We report here that hypoxia induces TSP-1 gene and protein expression. Oxygen tensions of < or =30 torr resulted in TSP-1 transcript induction initially apparent at 1 to 6 hours, with maximal induction (6.5-fold+/-1.2-fold) within 24 to 48 hours in both human and bovine endothelial cells. TSP-1 protein levels remain elevated after 72 hours of continuous hypoxic exposure. The induction of TSP-1 steady-state transcript levels is caused in large part, if not entirely, by post-transcriptional stabilization of the TSP-1 mRNA. The TSP-1 induction by hypoxia is a graded and reversible physiologic response and can be mimicked by the use of cobalt chloride or the inhibition of nitric oxide production, suggesting both the involvement of a heme-containing oxygen sensor and a role for the endogenous production of nitric oxide in TSP-1 regulation. The effects of hypoxia both on the stabilization of the TSP-1 transcript and the stimulation of TSP-1 protein production are completely inhibited by arginine butyrate.
Topics: Animals; Arginine; Butyrates; Cattle; Cells, Cultured; Cobalt; Cycloheximide; Dactinomycin; Endothelium, Vascular; Gene Expression Regulation; Humans; Hydroxamic Acids; Hypoxia; NG-Nitroarginine Methyl Ester; Oxygen; RNA, Messenger; Thrombospondin 1
PubMed: 9851743
DOI: 10.1016/s0022-2143(98)90131-7 -
Blood Cells, Molecules & Diseases Jun 1998Lymphoproliferative disorders associated with Epstein-Barr virus (EBV) infections can occur in the setting of immunosuppression. In some patients, the...
Lymphoproliferative disorders associated with Epstein-Barr virus (EBV) infections can occur in the setting of immunosuppression. In some patients, the lymphoproliferative disorder can resemble an aggressive monoclonal non-Hodgkins lymphoma (NHL). These NHL are poorly responsive to conventional therapy. Similarly, antiviral therapy with synthetic nucleosides such as ganciclovir are ineffective because the genes that render the virus susceptible to therapy are not expressed in EBV+ lymphomas. Using a cell line derived from a lung transplant recipient with an EBV+ immunoblastic NHL, we studied the ability of arginine butyrate to induce the expression of EBV thymidine kinase. Arginine butyrate was not only effective in inducing EBV thymidine kinase transcription, but also acted synergistically with the antiviral agent ganciclovir to inhibit cell proliferation and decrease cell viability. Based on these findings, the patient from whom the cell line was derived was treated with arginine butyrate/ganciclovir as well as conventional cytotoxic chemotherapy. No additional toxicity was observed with the arginine butyrate/ganciclovir therapy. Histologic examination of the tumor showed substantial necrosis. These observations suggest the feasibility of arginine butyrate induction of ganciclovir susceptibility in patients with EBV-associated lymphomas.
Topics: Antineoplastic Combined Chemotherapy Protocols; Antiviral Agents; Apoptosis; Arginine; Aspergillosis; Butyrates; Cyclophosphamide; Doxorubicin; Drug Synergism; Enzyme Induction; Epstein-Barr Virus Infections; Fatal Outcome; Ganciclovir; Gene Expression Regulation, Neoplastic; Gene Expression Regulation, Viral; Herpesvirus 4, Human; Humans; Lung Neoplasms; Lung Transplantation; Necrosis; Postoperative Complications; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Thymidine Kinase; Tumor Cells, Cultured; Vincristine; Viral Nonstructural Proteins
PubMed: 9628848
DOI: 10.1006/bcmd.1998.0178 -
Biochemical Pharmacology Mar 1996The anticancer drug cis-diamminedichloroplatinum(II) (cisplatin) has been shown previously to form adducts preferentially within internucleosomal or linker DNA rather...
The anticancer drug cis-diamminedichloroplatinum(II) (cisplatin) has been shown previously to form adducts preferentially within internucleosomal or linker DNA rather than to DNA within the nucleosome. To determine whether other "open" regions of chromatin have an increased affinity for cisplatin, adduct formation within specific chromatin domains was analyzed. There was a significant increase in cisplatin-DNA adduct formation for DNA associated with the nuclear matrix (NM) compared with other chromatin domains and total unfractionated DNA. In contrast, treatment of the same cells with trans-diamminedichloroplatinum(II) (transplatin) did not result in preferential adduct formation. These findings led to the hypothesis that it might be possible to alter DNA to make it a more favorable target for cisplatin. The effect of arginine butyrate on cisplatin-DNA adduct formation was analyzed in human cancer cells. The combination of arginine butyrate and cisplatin resulted in a concentration-responsive increase in cisplatin-DNA adduct formation in PC-3 cells and an overall increase in cisplatin-DNA adduct formation in three other human cancer cell lines. The same combination also resulted in a significant increase in drug-induced cytotoxicity at a low concentration of cisplatin. These results suggest that chromatin configuration can affect cisplatin adduct formation.
Topics: Antineoplastic Agents; Arginine; Butyrates; Chromatin; Cisplatin; DNA; DNA Adducts; Humans; Nucleic Acid Conformation; Tumor Cells, Cultured
PubMed: 8615910
DOI: 10.1016/s0006-2952(95)02256-2 -
The New England Journal of Medicine Jun 1995Enhanced production of fetal hemoglobin lessens the severity of beta-thalassemia and sickle cell disease. Intravenous infusion of arginine butyrate can increase the...
BACKGROUND
Enhanced production of fetal hemoglobin lessens the severity of beta-thalassemia and sickle cell disease. Intravenous infusion of arginine butyrate can increase the number of reticulocytes containing fetal hemoglobin in patients with these disorders, and it has induced a substantial increase in hemoglobin in one patient with thalassemia. We therefore tested the efficacy of this agent in patients with beta-hemoglobinopathies.
METHODS
We treated 10 patients with severe beta-thalassemia or sickle cell disease with arginine butyrate at an initial dose of 500 mg per kilogram of body weight per day (final dose, 2000 mg per kilogram per day), 6 days per week, for a mean (+/- SD) of 10 +/- 1.2 weeks (range, 9 to 13). A hematologic response was defined as an increase in the hemoglobin concentration of at least 2 g per deciliter in patients with thalassemia and as a twofold increase in the fetal hemoglobin concentration in patients with sickle cell disease.
RESULTS
Increase in gamma-globin messenger RNA and in reticulocytes containing fetal hemoglobin but not in hemoglobin were observed in the patients with thalassemia. A small, unsustained increase in fetal hemoglobin was observed in two patients with sickle cell disease. Drug toxicity was minimal at standard doses. One patient had a grand mal seizure after inadvertently receiving 2000 mg of arginine butyrate per kilogram over a period of six hours.
CONCLUSIONS
Ten weeks of intravenous arginine butyrate did not produce a hematologic response in 10 patients with either severe beta-thalassemia or sickle cell disease.
Topics: Adolescent; Adult; Anemia, Sickle Cell; Arginine; Biomarkers; Butyrates; Child; Child, Preschool; Female; Hemoglobins; Humans; Infusions, Intravenous; Male; beta-Thalassemia
PubMed: 7753139
DOI: 10.1056/NEJM199506153322404 -
Blood Oct 1994
Topics: Adult; Anemia, Sickle Cell; Arginine; Butyrates; Female; Hemoglobins, Abnormal; Humans; Leg Ulcer; Thalassemia
PubMed: 7919358
DOI: No ID Found -
Blood Sep 1994
Comparative Study
Topics: Adult; Amides; Arginine; Butyrates; Epilepsy; Fetal Hemoglobin; Humans; Phenylacetates; Phenylbutyrates; Reference Values; Valproic Acid
PubMed: 7520784
DOI: No ID Found