THE CHLOROETHYLNITROSOUREAS SENSITIVITY AND RESISTANCE TO CANCER-CHEMOTHERAPY AT THE MOLECULAR-LEVEL

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, espe cially the formation of a cytosine-guanine crosslink in DNA. Resistanc e occurs when the enzyme, O-6-alkylguanine-DNA alkyltransferase, repai rs an intermediate in crosslink formation. Inhibition of O-6-alkylguan ine-DNA alkyltransferase often restores sensitivity to the chloroethyl nitrosoureas although evidence is accumulating that other repair mecha nisms may also contribute to the resistance phenomenon. Continuing inv estigations in this field center on finding agents whose reactions wit h DNA are more specific, on elucidating other resistance mechanisms, a nd on overcoming resistance by developing new inhibitors of repair enz ymes.