QUENCHING OF DNA - PLATINUM(II) MONOADDUCTS AS A POSSIBLE MECHANISM OF RESISTANCE TO CIS-DIAMMINEDICHLOROPLATINUM(II) IN L1210-CELLS

Abstract

A line of mouse leukemia L1210 cells resistant to cis-diamminedichloroplatinum(II) (cis-DDP) was compared with its parent cell line to determine whether the sensitivity difference could be related to DNA interstrand cross-linking as meausured by the alkaline elution technique. The study was stimulated by a previous finding that the magnitude of DNA interstrand cross-linking, although somewhat reduced in this resistant line, did not account for the relatively high degree of resistance. Therefore, the kinetics of cross-link formation and removal was studied. Cross-link removal rates were determined by the use of thiourea to stop the delayed formation of interstrand cross-links from cis-DDP:DNA monoadducts. There was no significant difference between the cross-link removal rates in the parent and resistant lines. Computer-analyzed kinetics was consistent with an enhanced cis-DDP:DNA monoadduct quenching mechanisms in the resistant cells.