Nitrosoureas Modes of Action and Perspectives in the Use of Hormone Receptor Affine Carrier Molecules

Mechanisms of DNA adduct formation by antineoplastic 2-chloroethyl-N-nitrosoureas (CNUs) and of DNA damage induced by these compounds are discussed. CNUs are alkylating agents that form DNA-DNA cross-links as well as 2-chloroethylated and 2-hydroxyethylated adducts, the N-7-position of guanine being the predominantly alkylated site. A close correlation exists between the potential of a given compound to induce DNA-DNA cross-links and its antineoplastic effectiveness. However, levels of DNA-DNA cross-linking in bone marrow and extent of myelosuppression as measured in rodents are also closely correlated. The design of new cross-linking analogues capable of directing the antineoplastically relevant activity predominantly to the target tumour appears therefore to be of great promise. Cross-linking agents have been attached to a variety of steroid hormone carrier molecules and the conjugates have been tested in structure-activity studies using hormone-receptor containing animal tumours. These studies have revealed that some hormone-linked antineoplastic agents are highly effective in receptor positive experimental tumours and are superior to mixtures of unlinked alkylating agents with hormones. Indications for a relative enrichment of DNA damaging effects in the tumour tissue and for reduced myelotoxicity have been obtained with specific hormone conjugates.