Hypersensitivity of rat glioma sublines with acquired ACNU resistance to L-asparaginase

Yuji Saito M.D.1, Yosihiro Nakada Ph.D.1, Takuhiro Hotta M.D.1, Takasi Mikami M.D.1, Kaoru Kurisu M.D.1, Katuzou Kiya M.D.1, Keiichi Kawamoto Ph.D.1, and Tohru Uozumi M.D.1
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  • 1 Departments of Neurosurgery and Pharmacology, Hiroshima University School of Medicine, Minami-ku, Hiroshima, Japan
Page Range:
930–934
Volume/Issue:
Volume 75: Issue 6
DOI link:
https://doi.org/10.3171/jns.1991.75.6.0930
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✓ 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 × 105-fold. These results suggest that L-asparaginase therapy has the potential to become a new approach for treating acquired ACNU resistance.

Volume 75: Issue 6 (Dec 1991)

in Journal of Neurosurgery
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