We are continuing a project investigating the DNA base-sequence selectivity 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. DNA sequencing methodology was used to localize alkylations at guanine-N7 positions in a variety of procaryotic and eucaryotic DNA sequences. Marked differences in reaction intensities were observed at different guanines in a DNA sequence, as well as between different nitrogen mustards. Some of the differences in reaction intensities at different guanines may be due to sequence-dependent variations in the electrostatic potential at the guanine-N7 position. However, some nitrogen mustards, notably quinacrine mustard and uracil mustard have, in addition, unique and specific reactions at certain DNA sites. These and other sequence-dependent patterns are being investigated quantitatively.
