The Mayo Clinic-Canadian cooperative trial of sulfasalazine in active multiple sclerosis

Noseworthy, John H.; O’Brien, Peter C.; Erickson, Brandon J.; Lee, D.; Sneve, D.; Ebers, G. C.; Rice, G; Auty, Anthony; Hader, Walter; Kirk, Alan; Duquette, Pierre; Carter, J.; Francis, Gordon; Metz, L; Shuster, Elizabeth A.

doi:10.1212/wnl.51.5.1342

Cited by 87 publications

(40 citation statements)

References 17 publications

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“…These findings now warrant a more comprehensive assessment regarding the use of system x c Ϫ inhibitors in multiple glioma animal models, with a comprehensive pharmacokinetic assessment and thorough animal survival studies. Similarly, the pharmacokinetics and bioavailability of sulfasalazine and ( S)-4-CPG in the brain warrant additional assessment, although our data and findings from two previous studies suggest that sulfasalazine does effectively penetrate the blood-brain barrier in mice (Robe et al, 2004) and humans (Noseworthy et al, 1998). The additional pursuit of such studies is compelling in light of the paucity of effective treatments for malignant gliomas on the one hand, and the fact that sulfasalazine is already FDA approved, readily available, and backed by a large database of clinical data for other disease indications.…”

mentioning

confidence: 59%

Inhibition of Cystine Uptake Disrupts the Growth of Primary Brain Tumors

Chung¹,

Lyons²,

Nelson³

et al. 2005

J. Neurosci.

286

298

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Glial cells play an important role in sequestering neuronally released glutamate via Naϩ -dependent transporters. Surprisingly, these transporters are not operational in glial-derived tumors (gliomas). Instead, gliomas release glutamate, causing excitotoxic death of neurons in the vicinity of the tumor. We now show that glutamate release from glioma cells is an obligatory by-product of cellular cystine uptake via system x c Ϫ , an electroneutral cystine-glutamate exchanger. Cystine is an essential precursor for the biosynthesis of glutathione, a major redox regulatory molecule that protects cells from endogenously produced reactive oxygen species (ROS). Glioma cells, but not neurons or astrocytes, rely primarily on cystine uptake via system x c Ϫ for their glutathione synthesis. Inhibition of system x c Ϫ causes a rapid depletion of glutathione, and the resulting loss of ROS defense causes caspase-mediated apoptosis. Glioma cells can be rescued if glutathione status is experimentally restored or if glutathione is substituted by alternate cellular antioxidants, confirming that ROS are indeed mediators of cell death. We describe two potent drugs that permit pharmacological inhibition of system x c Ϫ . One of these drugs, sulfasalazine, is clinically used to treat inflammatory bowel disease and rheumatoid arthritis. Sulfasalazine was able to reduce glutathione levels in tumor tissue and slow tumor growth in vivo in a commonly used intracranial xenograft animal model for human gliomas when administered by intraperitoneal injection. These data suggest that inhibition of cystine uptake into glioma cells through the pharmacological inhibition of system x c Ϫ may be a viable therapeutic strategy with a Food and Drug Administration-approved drug already in hand.

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mentioning

confidence: 59%

Inhibition of Cystine Uptake Disrupts the Growth of Primary Brain Tumors

Chung¹,

Lyons²,

Nelson³

et al. 2005

J. Neurosci.

286

298

View full text Add to dashboard Cite

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“…Various recently published studies seem to show that the efficacy of IFN beta is greater when administered at a higher dose for a period between one and two years [7,8], although other studies do not confirm this observation [9]. In spite of all this, clinical trials in RRMS can produce erroneous clinical results, because of their short-term follow-up [10,11]. In addition, such results can be only partially reproduced ■ Abstract Background and objective Long-term observational studies may provide additional information about the behaviour of different drugs in the post-marketing period.…”

Section: Introductionmentioning

confidence: 99%

Interferon beta in relapsing–remitting multiple sclerosis

et al. 2005

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“…Previously, most such agents have not shown clear-cut benefits in this condition. [5][6][7][8][9][10] On the basis of a phase III clinical trial in Europe, 11,12 and an earlier phase II study, 13 mitoxantrone recently received an expanded indication from the Food and Drug Administration (FDA) for use in secondary progressive MS (SPMS), in progressiverelapsing MS, and for patients with worsening relapsing-remitting (RR) MS. This last category is defined as patients whose neurologic status remains significantly abnormal between MS attacks.…”

mentioning

confidence: 99%

The use of mitoxantrone (Novantrone) for the treatment of multiple sclerosis [RETIRED]

et al. 2003

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Abstract-Mitoxantrone is the first drug approved for the treatment of secondary progressive multiple sclerosis (SPMS) in the United States. This assessment considers use of mitoxantrone in the treatment of MS. Mitoxantrone probably reduces the clinical attack rate and reduces attack-related MRI outcomes in patients with relapsing MS (Type B recommendation). Also, mitoxantrone may have a beneficial effect on disease progression in patients with MS whose clinical condition is worsening (Type B recommendation). The potential for serious toxicity of mitoxantrone, however, must be taken into account when considering this therapy in individual patients. Moreover, because the potential clinical benefits on disease progression appear to be only modest, the results of the single phase III trial should be replicated in another (and hopefully much larger) clinical study before this agent is widely recommended for the treatment of patients with MS. NEUROLOGY 2003;61:1332-1338 Mitoxantrone hydrochloride (Novantrone) is an anthracenedione that has been used as an antineoplastic agent to treat hormone-refractory prostate cancer and acute nonlymphocytic leukemia in adults. It exerts its antineoplastic action by intercalating into DNA and producing both DNA strand-breaks and interstrand cross-links; it also interferes with RNA synthesis and markedly inhibits the enzyme topoisomerase II, which aids in the DNA repair process. [1][2][3][4] In the treatment of MS, mitoxantrone represents the latest in a long line of general immunosuppressive agents studied in this disease. Previously, most such agents have not shown clear-cut benefits in this condition. [5][6][7][8][9][10] On the basis of a phase III clinical trial in Europe, 11,12 and an earlier phase II study, 13 mitoxantrone recently received an expanded indication from the Food and Drug Administration (FDA) for use in secondary progressive MS (SPMS), in progressiverelapsing MS, and for patients with worsening relapsing-remitting (RR) MS. This last category is defined as patients whose neurologic status remains significantly abnormal between MS attacks.Mitoxantrone is the first drug approved for these indications in the United States, and it is the purpose of this assessment to consider both the evidence leading to the recent FDA approval as well as the appropriate clinical role of this agent in the management of patients with MS.Description of the analytic process. Articles for this review were searched in Medline under the keywords mitoxantrone and MS. Forty-one articles were identified by this search. The abstracts of these articles were reviewed and the original articles were selected for inclusion in the analysis only if they were either controlled trials or case series using mitoxantrone in the treatment of MS. Five such articles were identified, in addition to the phase III trial. 11,12 In addition, the reference lists of the articles found in this manner were also reviewed to identify articles or abstracts not found by the computer search.Analysis of the evidence. Followi...

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The Mayo Clinic-Canadian cooperative trial of sulfasalazine in active multiple sclerosis

Cited by 87 publications

References 17 publications

Inhibition of Cystine Uptake Disrupts the Growth of Primary Brain Tumors

Inhibition of Cystine Uptake Disrupts the Growth of Primary Brain Tumors

Interferon beta in relapsing–remitting multiple sclerosis

The use of mitoxantrone (Novantrone) for the treatment of multiple sclerosis [RETIRED]

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