The Chloroethylnitrosoureas: Sensitivity and Resistance to Cancer Chemotherapy at the Molecular Level

Abstract

The chloroethylnitrosoureas were developed in a synthetic program that began with the observation that N-methyl-N′-nitro-N-nitrosoguanidine was an effective agent against L1210 cells. The antitumor activity of the chloroethylnitrosoureas is based on their reactions with DNA, especially the formation of a cytosine-guanine crosslink in DNA. Resistance occurs when the enzyme, O⁶-alkylguanine-DNA alkyltransferase, repairs an intermediate in crosslink formation. Inhibition of O⁶-alkylguanine-DNA alkyltransferase often restores sensitivity to the chloroethlylnitrosoureas although evidence is accumulating that other repair mechanisms may also contribute to the resistance phenomenon. Continuing investigations in this field center on finding agents whose reactions with DNA are more specific, on elucidating other resistance mechanisms, and on overcoming resistance by developing new inhibitors of repair enzymes.