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Formation and Removal of DNA Cross-Links Induced by Melphalan and Nitrogen Mustard in Relation to Drug-induced Cytotoxicity in Human Melanoma Cells¹

Radiumhemmet, Karolinska Hospital, S-104 01 Stockholm, Sweden

The formation and removal of nitrogen mustard (HN2)- and melphalan-induced DNA cross-links (DNA interstrand and DNA-protein cross-links) in a human melanoma cell line (RPMI 8322), as determined by alkaline elution of DNA, was compared and related to the cytotoxic effect of each drug. HN2 was considerably more cytotoxic than melphalan as determined by inhibition of colony formation. Immediately following exposure to HN2 maximum levels of DNA cross-links were found. Melphalan, in contrast, caused a protracted induction of DNA cross-links with maximum levels obtained 6–12 h following drug exposure. HN2 induced approximately 13 times higher peak levels of DNA cross-links compared to equal concentrations of melphalan. Removal of DNA cross-links following exposure to both drugs followed an exponential time course. The rate of removal of HN2-induced DNA cross-links was, however, 1.5–2.4 times more rapid than that of melphalan-induced cross-links. A strong correlation was obtained between the cytotoxicity of both drugs and the total area under the curve for DNA interstrand cross-links, indicating that both the initial induction of as well as the rate of removal of DNA interstrand cross-links are important for the cytotoxic effects of bifunctional alkylating agents.

¹ This investigation was supported by King Gustaf V's Jubilee Foundation and the Swedish Cancer Society, Stockholm, Sweden.

² To whom requests for reprints should be addressed.

Received 10/20/86. Revised 2/ 4/87. Accepted 2/12/87.

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