Temozolomide selectively eliminates cancer stem cells in glioblastoma

摘要: 3208 Glioblastomas (GBM) are among the most aggressive human cancers with a median survival of 14.6 months despite multimodal therapy. Although today’s standard care - temozolomide significantly increases proportion patients surviving for more than two years, long-term survivors still rare exception. The biological properties cancer stem cells (CSC) maintaining GBM provide possible explanation failure chemotherapy in long term: CSC from several tumor entities overexpress multidrug resistance proteins which may protect them against cytotoxic drugs that kill progenitor and differentiated cells. would then give rise to recurrent tumors. However, although multiple authors have postulated this model, it has not yet been convincingly confirmed experimentally GBM.
 We therefore investigated effect on CD133+ CD133- lines (n=5) using an established vitro model cell lines. Surprisingly, induced dose- time-dependent decline rapidly proliferating subpopulation while constituting bulk all were resistant effects substance. Incubation sublethal concentrations 2 days eliminated clonogenic growth reduced tumorigenicity vivo.
 susceptibility was meditated by O6-methylguanine-DNA-methyltransferase (MGMT) but CD133 expression, MGMT promoter methylation status did differ between MGMT-expressing showed 10 fold higher reversible inhibitor 6-benzylguanidin.
 Despite selective elimination GBM, we found completely towards 5 µM corresponds peak concentration measured cerebrospinal fluid patients. While required eliminate positive (500 µM) can be reached patient, up 50 plasma patient after treatment sufficed negative tumors.
 these findings explain poor outcome tumors, is unclear why tumors die temozolomide. Considering impaired blood brain barrier infiltration otherwise healthy tissue much lower concentrations, postulate derive invading protected intact blood-brain barrier.
 Together, study will fundamentally change understanding bears important implications conception interpretation future past clinical trials.