FORMATION AND REPAIR OF 1,3-BIS-(2-CHLOROETHYL)-1-NITROSOUREA AND CISPLATIN-INDUCED TOTAL GENOMIC DNA INTERSTRAND CROSS-LINKS IN HUMAN GLIOMA-CELLS

The kinetics of formation and repair of total genomic DNA interstrand crosslinks (ISCs) induced by BCNU and cis-DDP were studied in cells of 6 human malignant gliomas and related with their degree of drug resis tance. DNA ISCs were formed rapidly (peak 6-12 h) following a 2 h expo sure to 50 mu M BCNU or 25 uM cis-DDP, and on an equimolar basis highe r levels of crosslinking were observed with cis-DDP than with BCNU. Re pair of cis-DDP induced crosslinks was characteristically bi-phasic an d the rate was significantly higher than that for BCNU induced crossli nks. Overall, a low crosslink index and a high crosslink repair rate c orrelated with cis-DDP and BCNU resistance. The data demonstrate, conc lusively, the ability of human glioma cells to repair cis-DDP and, for the first time, BCNU induced DNA ISCs and that DNA crosslink repair i s a significant contributing factor to the resistance of these tumors to the two agents.