TY - JOUR
T1 - Differential radiosensitizing potential of temozolomide in MGMT promoter methylated glioblastoma multiforme cell lines
AU - van Nifterik, Krista A
AU - van den Berg, Jaap
AU - Stalpers, Lukas J A
AU - Lafleur, M Vincent M
AU - Leenstra, Sieger
AU - Slotman, Ben J
AU - Hulsebos, Theo J M
AU - Sminia, Peter
PY - 2007/11/15
Y1 - 2007/11/15
N2 - PURPOSE: To investigate the radiosensitizing potential of temozolomide (TMZ) for human glioblastoma multiforme (GBM) cell lines using single-dose and fractionated gamma-irradiation.METHODS AND MATERIALS: Three genetically characterized human GBM cell lines (AMC-3046, VU-109, and VU-122) were exposed to various single (0-6 Gy) and daily fractionated doses (2 Gy per fraction) of gamma-irradiation. Repeated TMZ doses were given before and concurrent with irradiation treatment. Immediately plated clonogenic cell-survival curves were determined for both the single-dose and the fractionated irradiation experiments. To establish the net effect of clonogenic cell survival and cell proliferation, growth curves were determined, expressed as the number of surviving cells.RESULTS: All three cell lines showed MGMT promoter methylation, lacked MGMT protein expression, and were sensitive to TMZ. The isotoxic TMZ concentrations used were in a clinically feasible range of 10 micromol/L (AMC-3046), 3 micromol/L (VU-109), and 2.5 micromol/L (VU-122). Temozolomide was able to radiosensitize two cell lines (AMC 3046 and VU-122) using single-dose irradiation. A reduction in the number of surviving cells after treatment with the combination of TMZ and fractionated irradiation was seen in all three cell lines, but only AMC 3046 showed a radiosensitizing effect.CONCLUSIONS: This study on TMZ-sensitive GBM cell lines shows that TMZ can act as a radiosensitizer and is at least additive to gamma-irradiation. Enhancement of the radiation response by TMZ seems to be independent of the epigenetically silenced MGMT gene.
AB - PURPOSE: To investigate the radiosensitizing potential of temozolomide (TMZ) for human glioblastoma multiforme (GBM) cell lines using single-dose and fractionated gamma-irradiation.METHODS AND MATERIALS: Three genetically characterized human GBM cell lines (AMC-3046, VU-109, and VU-122) were exposed to various single (0-6 Gy) and daily fractionated doses (2 Gy per fraction) of gamma-irradiation. Repeated TMZ doses were given before and concurrent with irradiation treatment. Immediately plated clonogenic cell-survival curves were determined for both the single-dose and the fractionated irradiation experiments. To establish the net effect of clonogenic cell survival and cell proliferation, growth curves were determined, expressed as the number of surviving cells.RESULTS: All three cell lines showed MGMT promoter methylation, lacked MGMT protein expression, and were sensitive to TMZ. The isotoxic TMZ concentrations used were in a clinically feasible range of 10 micromol/L (AMC-3046), 3 micromol/L (VU-109), and 2.5 micromol/L (VU-122). Temozolomide was able to radiosensitize two cell lines (AMC 3046 and VU-122) using single-dose irradiation. A reduction in the number of surviving cells after treatment with the combination of TMZ and fractionated irradiation was seen in all three cell lines, but only AMC 3046 showed a radiosensitizing effect.CONCLUSIONS: This study on TMZ-sensitive GBM cell lines shows that TMZ can act as a radiosensitizer and is at least additive to gamma-irradiation. Enhancement of the radiation response by TMZ seems to be independent of the epigenetically silenced MGMT gene.
KW - Brain Neoplasms/enzymology
KW - Cell Line, Tumor
KW - Cell Proliferation/drug effects
KW - Cell Survival/drug effects
KW - Combined Modality Therapy/methods
KW - DNA Methylation
KW - Dacarbazine/analogs & derivatives
KW - Dose Fractionation
KW - Genes, Tumor Suppressor
KW - Glioblastoma/enzymology
KW - Humans
KW - Neoplasm Proteins/metabolism
KW - O(6)-Methylguanine-DNA Methyltransferase/metabolism
KW - Radiation Tolerance/drug effects
KW - Radiation-Sensitizing Agents/therapeutic use
KW - Xenograft Model Antitumor Assays/methods
U2 - 10.1016/j.ijrobp.2007.07.2366
DO - 10.1016/j.ijrobp.2007.07.2366
M3 - Article
C2 - 17967314
SN - 0360-3016
VL - 69
SP - 1246
EP - 1253
JO - International Journal of Radiation Oncology Biology Physics
JF - International Journal of Radiation Oncology Biology Physics
IS - 4
ER -