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Inhibition of the epidermal growth factor receptor tyrosine kinase activity by leflunomide
T Mattar1, K Kochhar, R Bartlett
1Department of Immunology, Johannes Gutenberg University, Mainz, Germany.
Abstract:
The active metabolite of leflunomide, A77 1726 inhibits the proliferation of a variety of mammalian cell lines in culture. Epidermal growth factor (EGF)-dependent proliferation is inhibited by A77 1726 at an effective dose of 30-40 microM. A77 1726 appears to directly inhibit the EGF receptor tyrosine-specific kinase activity both in intact cells and purified EGF receptors at the same effective dose. These data suggest that leflunomide inhibits cellular proliferation by the inhibition of tyrosine-specific kinase activities.
Insights
The active metabolite of leflunomide, A77 1726, blocks mammalian cell growth by inhibiting epidermal growth factor receptor tyrosine kinase activity. This discovery offers insights into leflunomide
Area of Science:
- Biochemistry
- Cell Biology
- Pharmacology
Background:
- Leflunomide is a disease-modifying antirheumatic drug used to treat rheumatoid arthritis.
- Its active metabolite, A77 1726, is known to have immunosuppressive effects.
Purpose of the Study:
- To investigate the mechanism by which A77 1726 inhibits mammalian cell proliferation.
- To determine if A77 1726 directly affects the epidermal growth factor (EGF) receptor signaling pathway.
Main Methods:
- Cell culture experiments using various mammalian cell lines.
- Assays to measure EGF-dependent proliferation.
- Enzyme activity assays on purified EGF receptors and intact cells.
Main Results:
- A77 1726 effectively inhibited the proliferation of multiple mammalian cell lines.
- EGF-dependent proliferation was suppressed by A77 1726 at concentrations of 30-40 microM.
- A77 1726 directly inhibited EGF receptor tyrosine kinase activity in both intact cells and purified receptors at the same effective dose.
Conclusions:
- Leflunomide's active metabolite, A77 1726, inhibits cell proliferation.
- The mechanism involves direct inhibition of EGF receptor tyrosine kinase activity.
- These findings suggest a role for tyrosine kinase inhibition in leflunomide's antiproliferative effects.