Abstract
Fifteen human glioma cell lines were examined for their sensitivity to 1,3-bis(chloroethyl)-nitrosourea (BCNU, carmustine) and cis-dichlorodiamminoplatinum (cisplatin), the induction of DNA interstrand cross-linking (DNA-ISC) induced by the two agents and cellular O6-alkylguanine alkyltransferase (ATase) activity. Cell lines differed in their sensitivities to BCNU by up to 12-fold and to cisplatin by up to 21-fold. For both drugs, the extent of DNA-ISC was related to the drug sensitivity. There was a wide range of cellular ATase levels. Increasing ATase levels correlated with increased resistance to BCNU and with decreased formation of DNA-ISC following treatment with BCNU. In contrast, following treatment with cisplatin, there was no correlation between cellular ATase content and cytotoxicity or between ATase and DNA-ISC. Four sublines of varying ATase activity were prepared from one of the cell lines. These sublines showed a sensitivity to BCNU in inverse proportion to ATase activity, while sensitivity to cisplatin was more uniform. The experiments confirm the direct relationship between ATase concentration and sensitivity to BCNU in glioma cells. Although there was some correlation between cisplatin cytotoxicity and BCNU cytotoxicity, this was not mediated through ATase.
Highlights
ATase levels were measured in 15 human glioma cell lines, their sensitivity to BCNU and cisplatin assessed and their relative DNAISC indices measured following treatment with the two agents
The sublines all remained relatively sensitive to treatment with cisplatin (Figure 3B), and all had a high level of DNA interstrand cross-linking (DNA-ISC) (Figure 3D). These results confirm that ATase levels vary in human glioma cell lines and that a high level of ATase correlates with resistance and decreased DNA-ISC formation in cell lines after treatment with
Cell lines with ATase level greater than 25 fmol mg-' protein were more resistant to BCNU and had fewer DNA interstrand crosslinks induced by this agent
Summary
Cell cultures were established from biopsy specimens of grade III and IV gliomas. One line was multiply passaged (passages 569-576) and 14 were early passage (passages 4-20). Four additional cell lines were prepared from a single line (SB) by plating one cell per well in a 96-well plate. ATase, DNA-ISC and cytotoxicity induced by BCNU and cisplatin 501 Cell line BCNU Cisplatin ATasea IC5(0M) CLI(50 gM) CLI (100 gM) IC1SO (gM).
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