A new project was undertaken to investigate the DNA base-sequence selctivity of alkylation reactions. The main objective is to determine whether base-sequence selectivities contribute to the anti-tumor activities of alkylating agents and whether the effectiveness of these drugs could be enhanced by structural modifications that would optimize the selectivity for certain sequences. A second objective is to utilize alkylation reactions to probe DNA structure and conformation in solution, especially with reference to the major groove. A DNA fragment being utilized in these studies contains the 5'-flank of the human c-H-ras-1 oncogene which contains a very GC-rich region, a possible hot-spot for alkylation reactions. DNA sequencing methodology was used to localize alkylations at guanine-N7 positions. Marked differences in reaction intensities were observed at different guanines in a DNA sequence, as well as between different nitrogen mustards. Some major sequence-dependent patterns were observed and are being investigated quantitatively.
