Abstract |
Immunosuppressive treatments of systemic lupus (SLE) remain associated with significant toxicities; hence, compounds with better toxicity profiles are needed. Dihydroorotate dehydrogenase ( DHODH) inhibition with leflunomide has proven to be effective in autoimmune diseases including SLE, but leflunomide can cause a variety of side effects. We hypothesized that 4SC-101, a novel DHODH inhibitor with a more favorable toxicity profile, would be as effective as high-dose cyclophosphamide (CYC) in controlling experimental SLE of female MRL(Fas)lpr mice. Daily oral gavage of 30, 100, and 300 mg/kg 4SC-101 from 12 to 22 weeks of age was compared with either vehicle or CYC treatment (30 mg/kg/week, i.p.) in terms of efficacy and toxicity. Three hundred milligrams per kilogram 4SC-101 was as effective as CYC in depleting spleen autoreactive T cells, B cells, and plasma cells as well as the respective DNA and RNA serum autoantibodies. This was associated with a comparable amelioration of the renal, dermal, and pulmonary SLE manifestations of MRL(Fas)lpr mice. However, even the highest dose of 4SC-101 had no effect on bone marrow neutrophil counts, which were significantly reduced in CYC-treated mice. Together, the novel DHODH inhibitor 4SC-101 is as effective as high dose CYC in controlling SLE without causing myelosuppression. Hence, DHODH inhibition with 4SC-101 might be suitable to treat active SLE with fewer side effects than CYC.
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Authors | Onkar P Kulkarni, Sufyan G Sayyed, Claudia Kantner, Mi Ryu, Max Schnurr, Miklós Sárdy, Johann Leban, Ruediger Jankowsky, Aldo Ammendola, Robert Doblhofer, Hans-Joachim Anders |
Journal | The American journal of pathology
(Am J Pathol)
Vol. 176
Issue 6
Pg. 2840-7
(Jun 2010)
ISSN: 1525-2191 [Electronic] United States |
PMID | 20413687
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Carboxylic Acids
- Dihydroorotate Dehydrogenase
- Immunosuppressive Agents
- Oxidoreductases Acting on CH-CH Group Donors
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Topics |
- Animals
- B-Lymphocytes
(drug effects, immunology)
- Carboxylic Acids
(chemistry, therapeutic use)
- Clinical Trials as Topic
- Dihydroorotate Dehydrogenase
- Disease Models, Animal
- Female
- Humans
- Immunosuppressive Agents
(chemistry, therapeutic use)
- Kidney
(cytology, drug effects, metabolism, pathology)
- Lupus Erythematosus, Systemic
(drug therapy, enzymology, immunology)
- Lupus Nephritis
(drug therapy, pathology)
- Mice
- Mice, Inbred MRL lpr
- Molecular Structure
- Oxidoreductases Acting on CH-CH Group Donors
(antagonists & inhibitors)
- T-Lymphocytes
(drug effects, immunology)
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