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Quenching of DNA:Platinum(II) Monoadducts as a Possible Mechanism of Resistance to cis-Diamminedichloroplatinum(II) in L1210 Cells

Laboratory of Molecular Pharmacology, Developmental Therapeutics Program, Division of Cancer Treatment, National Cancer Institute, NIH, Bethesda, Maryland 20205

A line of mouse leukemia L1210 cells resistant to cis-diamminedichloroplatinum(II) (cis-DDP) was compared with its parent cell line in order to determine whether the sensitivity difference could be related to DNA interstrand cross-linking as measured 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 mechanism in the resistant cells.

¹ To whom requests for reprints should be addressed, at Laboratory of Molecular Pharmacology, Developmental Therapeutics Program, Division of Cancer Treatment, National Cancer Institute, NIH, Building 37, Room 5D17, 9000 Rockville Pike, Bethesda, Md. 20205.

Received 11/15/82. Accepted 5/ 4/83.

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