Hypersensitivity of rat glioma sublines with acquired ACNU resistance to L-asparaginase.
Cell lines resistant to 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3- (2-chloroethyl)-3-nitrosourea hydrochloride (ACNU) show a high degree of collateral sensitivity to L-asparaginase. The mechanism for this phenomenon was investigated by comparing the nutritional requirements and asparagine synthetase activity of the resistant sublines to those of parent cells. Nine ACNU-resistant sublines were isolated from rat glioma 9L cells after incubation with various concentrations of ACNU in Ham's F-12 medium. The 9L cells grew independently of asparagine, developing well in asparagine-deficient Dulbecco's modified Eagle's medium. In contrast, the growth rates of all nine ACNU-resistant sublines decreased under the same conditions and required the addition of 10(-4) M asparagine for maximum growth. Asparagine synthetase activity in the ACNU-resistant cells was much lower than in the 9L cells, suggesting that the requirement for asparagine in the resistant sublines was due to reduced activity of this enzyme. A growth-inhibition assay showed that the ACNU-resistant sublines were more sensitive to L-asparaginase than 9L cells by up to 2 x 10(5)-fold. These results suggest that L-asparaginase therapy has the potential to become a new approach for treating acquired ACNU resistance.
Saito
Y
Y
Department of Neurosurgery, Hiroshima University School of Medicine, Japan.
Nakada
Y
Y
Hotta
T
T
Mikami
T
T
Kurisu
K
K
Kiya
K
K
Kawamoto
K
K
Uozumi
T
T
D000818:Animals; D001215:Asparaginase / Q000494:pharmacology*; D001216:Asparagine / Q000494:pharmacology; D001217:Aspartate-Ammonia Ligase / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D004351:Drug Resistance; D005910:Glioma / Q000188:drug therapy* / Q000201:enzymology; D015376:Nimustine / Q000627:therapeutic use*; D051381:Rats; D014407:Tumor Cells, Cultured / Q000187:drug effects
D015376:Nimustine; D001216:Asparagine; D001215:Asparaginase; D001217:Aspartate-Ammonia Ligase