Differential formation and enhanced removal of specific cisplatin-DNA adducts in two cisplatin-selected resistant human testicular teratoma sublines.
Mechanisms of cisplatin resistance have been studied in two independently-selected sublines expressing clinically-relevant levels of resistance (3-fold) and established from a primary testicular teratoma obtained from previously untreated patients. Resistance was not associated with any significant modification in cellular uptake of cisplatin, in total glutathione levels or associated enzyme activities. However, immunochemical quantitation of specific platinum-DNA adduct formation and removal revealed that both resistant sublines were more proficient in repairing certain adducts than their generally repair deficient respective parental lines. SUSA/CP+ cells were more efficient in removing the intrastrand adducts in the sequence Pt-AG and the bi-functional Pt-(GMP)2 lesions, as well as DNA-DNA interstrand cross-links, whilst H12.1/DDP cells were highly proficient in removing the major Pt-GG intrastrand adducts.
Hill
B T
BT
Laboratory of Cellular Chemotherapy, Imperial Cancer Research Fund, London, UK.
Shellard
S A
SA
Fichtinger-Schepman
A M
AM
Schmoll
H J
HJ
Harstrick
A
A
D002945:Cisplatin / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity; D018736:DNA Adducts / Q000378:metabolism*; D004249:DNA Damage; D004260:DNA Repair; D004351:Drug Resistance; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D005980:Glutathione Reductase / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D008297:Male; D013724:Teratoma / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism*; D013736:Testicular Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D018736:DNA Adducts; C057270:cisplatin-DNA adduct; D005979:Glutathione Peroxidase; D005980:Glutathione Reductase; D005982:Glutathione Transferase; D005978:Glutathione; D002945:Cisplatin