title: Efficacy of clinically relevant temozolomide dosing schemes in glioblastoma cancer stem cell lines.
abstract: The effectiveness of temozolomide (TMZ) dosing schemes and the "rechallenge" of recurrent glioblastoma (GBM) with TMZ are controversial. We therefore compared the efficacy of different TMZ dosing schemes against GBM cancer stem cell (CSC) lines in vitro. In O(6)-methyl-guanidine-methyl-transferase (MGMT)-negative CSC lines, all schedules (1 day on/27 days off, 5 days on/23 days off, 7 days on/7 days off, 21 days on/7 days off, continuous low-dose TMZ) depleted clonogenic cells. In TMZ-resistant CSC lines, the 7 days on/7 days off scheme showed higher toxicity as compared with the other schemes. However, clinically feasible concentrations remained ineffective in highly resistant CSC lines. In addition, none of the schedules induced long-term depletion of clonogenic cells even at the highest concentrations (up to 250 μM). After sublethal TMZ treatment for 5 days, TMZ rechallenge of recovering CSC lines remained effective. Our data advocate CSC lines as in vitro model to address clinical questions. Using this model, our data suggest the effectiveness of TMZ in MGMT-negative CSC lines and support the concept of TMZ rechallenge. The 7 days on/7 days off scheme consistently showed the best activity of all schedules in TMZ-resistant CSC lines.
authors.affiliation: Department of Neurology and JARA Brain, Hospital Medical School, RWTH Aachen University, Pauwelsstrasse 30, 52074, Aachen, Germany.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Beier
authors.forename: Beate
authors.initials: B
authors.lastname: Schriefer
authors.forename: Konstantin
authors.initials: K
authors.lastname: Brawanski
authors.forename: Peter
authors.initials: P
authors.lastname: Hau
authors.forename: Joachim
authors.initials: J
authors.lastname: Weis
authors.forename: Jörg B
authors.initials: JB
authors.lastname: Schulz
authors.forename: Christoph P
authors.initials: CP
authors.lastname: Beier
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D015254:DNA Modification Methylases / Q000378:metabolism; D045643:DNA Repair Enzymes / Q000378:metabolism; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005434:Flow Cytometry; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000077204:Temozolomide; D014410:Tumor Stem Cell Assay; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D018906:Antineoplastic Agents, Alkylating; D025521:Tumor Suppressor Proteins; D003606:Dacarbazine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes; D000077204:Temozolomide