Current drugs available now for interleukin-6 suppression as treatment adjunct in glioblastoma: Anakinra, aprepitant, mirtazapine and olanzapine

Glioblastoma is a particularly aggressive cancer for which there are no good treatments as of autumn 2005. Mortality several years after diagnosis approaches 100%. This research summarizes evidence that a) most glioblastomas synthesize and secrete interleukin-6, b) that interleukin-6 is a significant growth and survival factor for these cells and c) that glioblastoma cells are stimulated to increase their interleukin-6 production by histamine acting on H1 receptors or by constitutive H1 receptor activity even in absence of ligand (histamine). New and unusually potent antihistamines (inverse agonists) are currently on the market (mirtazapine, olanzapine). Other less potent H1 antihistamines have been shown to inhibit interleukin-6 synthesis in other cell systems in vitro and when used clinically in humans in the upper airway. Mirtazapine and olanzapme inhibit both constitutive and ligand stimulated H1 receptor activity. They might also thereby inhibit glioblastoma's interleukin-6 synthesis. By thus depriving glioblastoma of a growth factor these antihistamines may slow this ferocious cancer's growth. Substance P and interleukin- 1 beta have been also shown to stimulate interleukin-6 synthesis in some systems. Aprepitant is an oral substance P antagonist on the market to treat nausea and vomiting of cancer chemotherapy and anakinra is a parenteral interleukin- 1 inhibitor on the market to treat rheumatoid arthritis- it is suggested that these be given as well in the attempt to deprive glioblastomas of interleukin-6. There are other cancers that are partially driven by il-6 acting as a growth factor- for example colon cancer, melanoma, multiple myeloma and prostate cancer. If these drugs really do lower interleukin-6 levels and hence il-6 signaling, they should be tried in these cancers as well.