The role of DNA repair in resistance of L1210 cells to isomeric 1,2-diaminocyclohexaneplatinum complexes and ultraviolet irradiation.
Resistance to cisplatin in several murine leukemia L1210 cell lines is due to enhanced DNA repair. Other platinum complexes, particularly those containing 1,2-diaminocyclohexane (DACH) are of interest as they effectively kill both sensitive (L1210/0) and cisplatin-resistant (L1210/DDP) cell lines. An L1210/DACH cell line has been developed that is preferentially resistant to DACH-Pt complexes. In the current experiments, we investigated the role that DNA repair has in resistance to DACH-Pt compounds. The DACH ligand exists in 3 isomeric forms which exhibit markedly different activities in the various resistant cell lines. Generally, R,R-DACH-Pt was the most effective isomer. DNA repair was assayed by host-cell reactivation of platinated pRSVcat. DNA damage induced by all the isomeric DACH-Pt-SO4 complexes markedly reduced CAT expression in sensitive L1210/0 cells. One adduct per transcribed strand of the cat gene inhibited CAT expression demonstrating that the sensitive cells exhibited no detectable DNA repair. All the resistant cell lines reactivated the plasmid DNA whether damaged with cisplatin or any of the 3 DACH-Pt isomers. Therefore, resistance to both cisplatin and DACH-Pt appears to be mediated by enhanced DNA repair, but the level of reactivation of the transfected plasmid did not correlate with the toxicity of each analogue. These results suggest that some additional event(s) is responsible for the substrate specificity of repair of genomic DNA. These resistant cell lines also exhibited resistance to UV irradiation but this was much less than, and did not correlate with the degree of resistance to either cisplatin or DACH-Pt. However, there was a good correlation between resistance to UV irradiation and reactivation of UV-damaged plasmid DNA. This enhanced reactivation suggests that enhanced repair may be the sole reason for the resistance to UV irradiation.
Jennerwein
M M
MM
Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, NH 03756.
Eastman
A
A
Khokhar
A R
AR
D000818:Animals; D002945:Cisplatin / Q000633:toxicity; D004249:DNA Damage; D004260:DNA Repair; D004351:Drug Resistance / Q000235:genetics; D007939:Leukemia L1210; D051379:Mice; D009944:Organoplatinum Compounds / Q000633:toxicity*; D010957:Plasmids; D013379:Substrate Specificity; D014162:Transfection; D014407:Tumor Cells, Cultured; D014466:Ultraviolet Rays
D009944:Organoplatinum Compounds; C013933:dichloro-1,2-diaminocyclohexane platinum complex; D002945:Cisplatin