O6-alkylguanine-DNA alkyltransferase activity of human malignant glioma and its clinical implications.
Activity of the DNA repair protein O6-alkylguanine-DNA alkyltransferase (AGT) is an important determinant of responsiveness of tumor cells to chloroethylnitrosoureas (CENUs), representative chemotherapeutic agents for primary malignant gliomas. In order to assess the real states of this repair protein in human malignant gliomas, we assayed AGT activity in surgically extirpated 42 malignant glioma samples and studied the distribution of the activity under certain clinical conditions. There were wide variations in AGT activity between individuals. No significant difference in AGT activity on average was seen either between glioblastoma and anaplastic astrocytoma, nor between primary and recurrent tumors. Among 42 malignant gliomas, 7 samples (16.7%) had low AGT activity less than 0.1 pmoles/mg protein. In the case of glioblastoma, tumors possessing higher AGT activity tended to be less responsive to post-operation remission-induction therapy including CENUs. The result of the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) chemosensitivity assay by using the corresponding surgical specimens suggested a close relationship between cellular resistance to CENUs and AGT activity. It was found to be unlikely that a short term administration of CENUs had a significant effect on AGT activity of brain tumors in human body. We could detect a bit of definite evidences of the relevance of AGT to resistance to CENUs and need to conduct further investigations for other resistance factors.
Hotta
T
T
Department of Neurosurgery, Hiroshima University School of Medicine, Japan.
Saito
Y
Y
Fujita
H
H
Mikami
T
T
Kurisu
K
K
Kiya
K
K
Uozumi
T
T
Isowa
G
G
Ishizaki
K
K
Ikenaga
M
M
D001254:Astrocytoma / Q000188:drug therapy / Q000201:enzymology / Q000601:surgery; D001932:Brain Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology / Q000601:surgery; D003131:Combined Modality Therapy; D004249:DNA Damage; D004260:DNA Repair; D004273:DNA, Neoplasm / Q000187:drug effects; D004351:Drug Resistance; D004790:Enzyme Induction / Q000187:drug effects; D005909:Glioblastoma / Q000188:drug therapy / Q000201:enzymology / Q000601:surgery; D005910:Glioma / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology / Q000601:surgery; D006801:Humans; D008780:Methyltransferases / Q000032:analysis*; D009363:Neoplasm Proteins / Q000032:analysis*; D009364:Neoplasm Recurrence, Local / Q000201:enzymology; D015376:Nimustine / Q000494:pharmacology / Q000627:therapeutic use*; D009607:Nitrosourea Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D019853:O(6)-Methylguanine-DNA Methyltransferase; D013778:Tetrazolium Salts; D013844:Thiazoles
D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D009607:Nitrosourea Compounds; D013778:Tetrazolium Salts; D013844:Thiazoles; D015376:Nimustine; D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase; C022616:thiazolyl blue; C020766:ranimustine