memantine + temozolomide

The combination of memantine and temozolomide has been studied as a treatment approach for glioblastoma multiforme (GBM), a type of brain cancer. This combination was investigated in a phase 1 factorial study to determine the maximum tolerated doses when used together. Memantine is an NMDA receptor antagonist that has neuroprotective properties and is typically used for treating Alzheimer's disease. Temozolomide is a prodrug that undergoes nonenzymatic hydrolysis at physiological pH to perform alkylation of DNA, leading to DNA damage and eventual cell death. It's primarily indicated for treating newly diagnosed glioblastoma concomitantly with radiotherapy and as maintenance treatment thereafter. When combined, memantine was found to be safe at 20 mg twice daily with temozolomide (doublet therapy), and at 10 mg twice daily when used in triplet or quadruplet combinations that included mefloquine and/or metformin. The combination therapy showed promising results in the phase 1 study, with a median survival of 21 months from study entry and a 2-year survival rate of 43%. The most common adverse events included lymphopenia (66%) and fatigue (65%), with specific dose-limiting toxicities including dizziness related to memantine and gastrointestinal effects related to metformin. This combination approach represents an interesting strategy of repurposing non-cancer drugs (memantine, mefloquine, and metformin) that have putative anticancer activity for the treatment of glioblastoma.