INCREASED GENE-SPECIFIC REPAIR OF CISPLATIN-INDUCED INTERSTRAND CROSS-LINKS IN CISPLATIN-RESISTANT CELL-LINES, AND STUDIES ON CARRIER LIGAND SPECIFICITY

Development of resistance to cisplatin in previously treatment-respons ive malignancies is a major obstacle to successful treatment, Enhanced DNA repair as well as enhanced replicative bypass of DNA adducts have been suggested to play a role in the development of resistance to cis platin, However, the relative contribution of these mechanisms is unkn own, Second generation platinum compounds containing the 1,2-diaminocy clohexane (dach) carrier ligand have been of particular interest in th e studies of resistance mechanisms since they have been effective in t reatment of cells resistant to cisplatin, We have investigated the for mation and repair of interstrand crosslinks (ICL) in the mouse leukemi a cell line L1210/0 and its carrier ligand specific resistant derivati ves L1210/DDP and L1210/DACH after treatment with ethylenediamine (en) -Pt and diaminocyclohexane (dach)-Pt compounds, ICL in the overall gen ome were examined using a modification of the alkaline elution assay, A Southern blot technique was employed for the study of ICL in specifi c regions of the genome. In the overall genome we found decreased form ation of ICL with either -en or -dach carrier ligands in the two resis tant cell lines without carrier ligand specificity, Some carrier ligan d specificity of ICL formation was observed in the dihydrofolate reduc tase (DHFR) gene, but it did not correlate with the carrier ligand spe cificity of resistance. At the level of the overall genome there was n o difference in repair of ICL between the sensitive and the two resist ant cell lines, When measured in the DHFR gene, however, there was enh anced repair of ICL in the two resistant cell lines compared with the sensitive cell line, The enhanced repair at the level of the gene did not display any carrier ligand specificity.