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DNA Cross-Linking and Cytotoxicity Induced by cis-Diamminedichloroplatinum(II) in Human Normal and Tumor Cell Lines

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

We have studied the cytotoxicity and DNA cross-linking induced by cis-diamminedichloroplatinum(II) (cis-Pt) in a normal, a simian virus 40-transformed, and eight tumor cell lines of human origin. These cell strains were chosen on the basis of their Mer phenotype, i.e., their ability to repair DNA containing ⁶O-alkylated guanine.

The cytotoxicity was assayed by measuring the inhibition of cell proliferation after a two-hr treatment of the cell cultures with cis-Pt concentrations ranging from 1 to 50 µM. DNA-protein cross-links and DNA interstrand cross-links were measured by DNA alkaline elution after a two-hr treatment with 10 or 20 µM cis-Pt.

The different cell lines differed in sensitivity to cis-Pt. The drug concentration required to produce the same inhibition of growth varied over a 10-fold range. Cell sensitivity correlated with DNA interstrand cross-linking (r = 0.83; p < 0.01) better than with DNA-protein cross-linking (r = 0.75; p < 0.05). There was no correlation between cell sensitivity or DNA interstrand cross-linking and the Mer phenotype.

The lack of relationship between the extent of DNA interstrand cross-linking by cis-Pt and the Mer phenotype suggests that this repair mechanism does not remove from DNA cis-Pt monoadducts that have the potential to form interstrand crosslinks.

¹ Recipient of grants from the Fogarty International Center (NIH) and the Rose and Jean Hoguet Foundation. Present address: Universite de l'Etat a Mons, avenue du Champs de Mars, 24, Faculte de Medecine, Service de Biochimie Moleculaire B-7000, Mons, Belgium.

² To whom requests for reprints should be addressed, at Building 37, Room 5D17, NIH, Bethesda, Md. 20205.

Received 2/20/81. Accepted 6/ 2/81.