DNA interstrand cross-linking and cytotoxicity induced by chloroethylnitrosoureas and cisplatin in human glioma cell lines which vary in cellular concentration of O6-alkylguanine-DNA alkyltransferase.
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.
Beith
J
J
Department of Oncology, University College London Medical School, UK.
Hartley
J
J
Darling
J
J
Souhami
R
R
D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000201:enzymology*; D002330:Carmustine / Q000378:metabolism / Q000494:pharmacology*; D002945:Cisplatin / Q000378:metabolism / Q000494:pharmacology*; D018736:DNA Adducts / Q000378:metabolism; D004273:DNA, Neoplasm / Q000378:metabolism*; D004354:Drug Screening Assays, Antitumor; D005910:Glioma / Q000188:drug therapy* / Q000201:enzymology*; D006801:Humans; D008780:Methyltransferases / Q000032:analysis*; D009363:Neoplasm Proteins / Q000032:analysis*; D019853:O(6)-Methylguanine-DNA Methyltransferase; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D018736:DNA Adducts; D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase; D002945:Cisplatin; D002330:Carmustine