Differential formation and enhanced removal of specific cisplatin-DNA adducts in two cisplatin-selected resistant human testicular teratoma sublines.

ABSTRACT

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.