bortezomib + temozolomide

A combination therapy consisting of bortezomib, a proteasome inhibitor, and temozolomide, an alkylating agent. This combination is primarily investigated for the treatment of glioblastoma multiforme (GBM). ## Mechanism of Action Bortezomib is a proteasome inhibitor that works by blocking the 26S proteasome, a protein complex responsible for degrading ubiquitinated proteins. This inhibition leads to cell cycle arrest and apoptosis in cancer cells. Temozolomide is an alkylating agent that damages DNA through methylation, particularly at the O6 position of guanine, leading to cell death. The combination appears to work synergistically through several mechanisms: 1. Bortezomib depletes the O6-methylguanine DNA methyltransferase (MGMT) enzyme, which normally repairs DNA damage caused by temozolomide, thereby potentially restoring tumor sensitivity to temozolomide. 2. Bortezomide inhibits temozolomide-induced autophagic flux, which is a survival mechanism that cancer cells use to resist chemotherapy. 3. The combination enhances DNA double-strand breaks and increases apoptosis compared to either agent alone. ## Clinical Development This combination has been studied in both newly diagnosed and recurrent glioblastoma patients. In phase II clinical trials, bortezomib (1.3 mg/m²) was administered on specific days during radiation therapy with concurrent temozolomide, followed by adjuvant bortezomib and temozolomide for up to 24 cycles. The combination has shown promising results, particularly in patients with MGMT methylated tumors, with median progression-free survival of 24.7 months compared to 5.1 months in unmethylated patients. The overall survival rates at various timepoints (12, 24, and 36-60 months) appeared improved compared to historical norms. ## Administration Temozolomide is administered orally in capsule form, while bortezomib is given as an injection either intravenously or subcutaneously. In clinical trials, bortezomib was typically given at 1.3 mg/m² on days 1, 4, 8, and 11 of a 28-day cycle, while temozolomide was administered at 150-200 mg/m²/day for 5 days every 28 days. The combination has been reported to be generally well-tolerated, with no unexpected adverse events from the addition of bortezomib to standard temozolomide treatment.