DNA INTERSTRAND CROSS-LINKING AND CYTOTOXICITY INDUCED BY CHLOROETHYLNITROSOUREAS AND CISPLATIN IN HUMAN GLIOMA CELL-LINES WHICH VARY IN CELLULAR CONCENTRATION OF O-6-ALKYLGUANINE-DNA ALKYLTRANSFERASE

Fifteen human glioma cell lines were examined for their sensitivity to 1,3-bis(chloroethyl)-nitrosourea (BCNU, carmustine) and cis-dichlorod iamminoplatinum (cisplatin), the induction of DNA interstrand cross-li nking (DNA-ISC) induced by the two agents and cellular O-6-alkylguanin e alkyltransferase (ATase) activity. Cell lines differed in their sens itivities to BGNU 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 sensitiv ity. There was a wide range of cellular ATase levels. Increasing ATase levels correlated with increased resistance to BGNU and with decrease d formation of DNA-ISC following treatment with BCNU. In contrast, fol lowing treatment with cisplatin, there was no correlation between cell ular 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 proport ion to ATase activity, while sensitivity to cisplatin was more uniform . The experiments confirm the direct relationship between ATase concen tration and sensitivity to BGNU in glioma cells. Although there was so me correlation between cisplatin cytotoxicity and BCNU cytotoxicity, t his was not mediated through ATase.