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Differences in the in Vivo Alkylation and Cross-linking of Nitrogen Mustard-sensitive and -resistant Lines of Lettré-Ehrlich Ascites Tumors¹

Department of Chemistry, University of Pennsylvania, and Division of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104

Two lines of Ehrlich ascites tumors showing a 10- to 50-fold difference in sensitivity to nitrogen mustard (HN2) have been compared as to the extent of alkylation and cross-linking of their DNA. The resistant line (L2RA) shows approximately half the alkylation and half the cross-linking of the sensitive line (LES) after 60 minutes of exposure to HN2 in vivo. The alkylation and cross-linking functions have been shown to be proportional to the HN2 dosage; a linear relation exists between alkylation and cross-linking so that 7–8% of the DNA is cross-linked per alkylation, in agreement with predictions from the frequency of GpC (S' 3' base sequence in DNA; G, guanine; C, cytosine) sequences in mammalian DNA. No threshold effects are observed for alkylation or cross-linking at low doses of HN2, the reaction being primarily if not entirely governed by the reactivity of the guanine in the native, in vivo structure. The data are fully consistent with the original cross-linking hypothesis as the mechanism of action of bifunctional alkylating agents but are not consistent with lethal mutation hypotheses of cytotoxicity. The resistance of the Ehrlich cells can be partially explained by the selection by HN2 of cells less permeable to the drug, but the extent of resistance acquired during selection requires the intervention of a more elaborate set of cellular changes.

¹ This work was supported by Grant No. CA 05295 from the USPHS.

Received 7/24/68. Accepted 1/30/69.