[Circumvention of ACNU-resistance in rat glioma cells by pretreatment with O6-methylguanine].
The chemotherapy of malignant brain tumors has been, only partially successful yet. Recently major concern is drug resistance, one of possible mechanisms of such drug resistance stems from inducible repair enzyme, especially in case of chloroethylnitrosoureas as ACNU or BCNU. We examined the changes of acquired resistance to ACNU in rat glioma cells by pretreatment with O6-methylguanine, which is a substrate for O6-methylguanine methyltransferase. ACNU-resistant (9L/AC) cells had established after 10 times treatments of ACNU. 9L/AC cells were pretreated with 2 mM O6-methylguanine for 2 hours, and subsequently challenged with increasing doses of ACNU for 2 hours. In vitro colony formation assay the survival fraction of 9L and 9L/AC cells ranged from 0.39 to 0.63 by 2-hour reaction of 1-3 mM O6-methylguanine. Based on the dose-response curve for ACNU in 9L/AC cells, by O6-methylguanine pretreatment (2 mM), ACNU-resistance decreased markedly to one-third, one-fifth, and one-two hundredth at 12, 24, 36 microM ACNU, respectively. In contrast, the survival of 9L cells against ACNU was similar under O6-methylguanine pretreatment or nontreatment condition. Therefore, ACNU-resistance is considerably related to DNA repair enzyme induction, and the substrates may potentiate the cell-killing effect of ACNU in the resistant glioma cells.
Mineura
K
K
Neurosurgical Service, Akita University Hospital, Japan.
Fushimi
S
S
Sasaki
J
J
Sasajima
H
H
Ishino
Y
Y
Kowada
M
M
D000818:Animals; D001932:Brain Neoplasms / Q000201:enzymology / Q000473:pathology*; D002470:Cell Survival; D004351:Drug Resistance; D004357:Drug Synergism; D004790:Enzyme Induction; D005910:Glioma / Q000201:enzymology / Q000473:pathology*; D006147:Guanine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008780:Methyltransferases / Q000096:biosynthesis; D015376:Nimustine / Q000494:pharmacology*; D019853:O(6)-Methylguanine-DNA Methyltransferase; D051381:Rats; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000201:enzymology; D014410:Tumor Stem Cell Assay
D015376:Nimustine; D006147:Guanine; C008449:O-(6)-methylguanine; D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase