Increased gene specific repair of cisplatin induced interstrand crosslinks in cisplatin resistant cell lines, and studies on carrier ligand specificity.
Development of resistance to cisplatin in previously treatment-responsive 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 cisplatin. However, the relative contribution of these mechanisms is unknown. Second generation platinum compounds containing the 1,2-diaminocyclohexane (dach) carrier ligand have been of particular interest in the studies of resistance mechanisms since they have been effective in treatment of cells resistant to cisplatin. We have investigated the formation and repair of interstrand crosslinks (ICL) in the mouse leukemia cell line L1210/0 and its carrier ligand specific resistant derivatives L1210/DDP and L1210/DACH after treatment with ethylenediamine (en)-Pt and diaminocyclohexane (dach)-Pt compounds. ICL in the overall genome were examined using a modification of the alkaline elution assay. A Southern blot technique was employed for the study of ICL in specific regions of the genome. In the overall genome we found decreased formation of ICL with either -en or -dach carrier ligands in the two resistant cell lines without carrier ligand specificity. Some carrier ligand specificity of ICL formation was observed in the dihydrofolate reductase (DHFR) gene, but it did not correlate with the carrier ligand specificity of resistance. At the level of the overall genome there was no difference in repair of ICL between the sensitive and the two resistant cell lines. When measured in the DHFR gene, however, there was enhanced 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.
Petersen
L N
LN
Laboratory of Molecular Genetics, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA.
Mamenta
E L
EL
Stevnsner
T
T
Chaney
S G
SG
Bohr
V A
VA
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002945:Cisplatin / Q000378:metabolism / Q000494:pharmacology*; D003514:Cyclohexylamines / Q000378:metabolism*; D004247:DNA / Q000378:metabolism; D004260:DNA Repair; D004337:Drug Carriers; D004351:Drug Resistance; D008024:Ligands; D051379:Mice; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D003514:Cyclohexylamines; D004337:Drug Carriers; D008024:Ligands; D004247:DNA; C030435:1,2-cyclohexanediamine; D013762:Tetrahydrofolate Dehydrogenase; D002945:Cisplatin