This project investigates the molecular selectivity of alkylating agents and other DNA-reactive drugs and explores the factors that govern selective cell killing by these drugs. (1) A systematic study was conducted of a series of acridine nitrogen mustards, prepared under DTP contract. These intercalating mustards are nearly as active in monofunctional as in bifunctional form and do not have to crosslink DNA to be active. The DNA sequence selectivity of these compounds was found to depend on the length of the connecting chain between the acridine and nitrogen mustard moieties. The optimum selective monofunctional derivative with a connecting chain length of 3 is a potential candidate for drug development. (2) The DNA sequence environment that favors interstrand crosslinking by various nitrogen mustards was studies using designed synthetic oligonucleotides. A major finding was that isophoramide mustard is more efficient than other standard nitrogen mustards in interstrand and crosslinking. (3) The mechanism by which DNA crosslinking leads to cell death is being studied in Burkitt lymphoma cells that we had previously found to differ in sensitivity to HN2, but which were alike with respect to the production and repair of interstrand and DNA-protein crosslinks. Following treatment with HN2, the cells exhibited G2 delay and, at higher doses, retardation of DNA synthesis. The changes in the cyclin/cdc2 kinase system associated with G2 and mitosis are being investigated in order to localize the difference between the cell lines at the molecular level. So far, we have found that the difference resides prior to the suppression of cdc2 kinase activity.
