In vitro evaluation of temozolomide combined with X-irradiation.
The in vitro cytotoxicity of 8-carbamoyl-3-methylimidazo [5,1-d]-1,2,3,5-tetrazine-4(3H)-one (temozolomide) with concurrent X-irradiation was examined in a human glioblastoma cell line (U373MG) as a potential radio-chemotherapeutic treatment for malignant glioma. The combination was also examined in a human colorectal adenocarcinoma (Mawi) which had 100-fold greater O6-alkylguanine-DNA alkyltransferase (AGT) activity, a DNA-repair protein which confers resistance to temozolomide. A comparison of IC50 values indicated U373MG to be over 32-fold more sensitive to temozolomide than Mawi, but slightly more resistant to X-irradiation (p < 0.035; unpaired two-tailed t-test). Temozolomide and X-irradiation proved largely additive in U373MG by isobologram analysis (50% iso-effect) and the addition of 10 microM temozolomide to 1-2 Gy of X-irradiation increased cell kill by 2.5- to 3.0-fold. However, the combination was antagonistic in Mawi: an effect attributed to AGT induction by X-irradiation as the antagonism was removed by co-incubation with the AGT inhibitor O6-benzylguanine (O6-BG 1 microM; 24 h). O6-BG did not affect the radiation dose-response curve, but significantly increased temozolomide cytotoxicity (p < 0.015). In conclusion, the combination of temozolomide with radiation is at best additive, but could nonetheless by of considerable therapeutic benefit in glioma, particularly if administered for prolonged periods. If AGT induction compromises the efficacy of this therapy, it may be circumvented with an appropriate inhibitor such as O6-BG.
Wedge
S R
SR
Department of Medical Oncology, Charing Cross Hospital, London, UK.
Porteous
J K
JK
Glaser
M G
MG
Marcus
K
K
Newlands
E S
ES
D000230:Adenocarcinoma / Q000188:drug therapy / Q000532:radiotherapy / Q000628:therapy*; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000532:radiotherapy / Q000628:therapy*; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000532:radiotherapy / Q000628:therapy*; D003131:Combined Modality Therapy; D018736:DNA Adducts / Q000187:drug effects / Q000378:metabolism; D004260:DNA Repair / Q000187:drug effects; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005909:Glioblastoma / Q000188:drug therapy / Q000532:radiotherapy / Q000628:therapy*; D006801:Humans; D008780:Methyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D019853:O(6)-Methylguanine-DNA Methyltransferase; D000077204:Temozolomide; D014407:Tumor Cells, Cultured
D018906:Antineoplastic Agents, Alkylating; D018736:DNA Adducts; D003606:Dacarbazine; D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase; D000077204:Temozolomide