Differences between melphalan and nitrogen mustard in the formation and removal of DNA cross-links.

The formation of DNA cross-links is thought to represent the lethal lesion following exposure of cells to bifunctional alkylating agents. Since differences in rates of formation and repair of cross-links may explain differences in activity of these agents, we have studied these events following exposure of L1210 cells to nitrogen mustard (HN2) and melphalan. With the technique of alkaline elution, it was possible to measure cross-linking at doses that result in relatively little cell kill. Following a 30-min exposure to HN2, DNA cross-links increased for 1 to 2 hr and were then removed by a process that was virtually complete in 24 hr. In contrast, following a 30-min exposure to melphalan, cross-link formation increased for 12 hr and removal was much slower than it was for HN2. Comparison of cell survival with cross-linking kinetics suggests that persistence of the cross-links with time is an important factor in determining lethality.