Nitrosoureas. Modes of action and perspectives in the use of hormone receptor affinity 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.
Eisenbrand
G
G
Department of Food Chemistry and Environmental Toxicology, University of Kaiserslautern, West Germany.
Berger
M R
MR
Brix
H P
HP
Fischer
J E
JE
Mühlbauer
K
K
Nowrousian
M R
MR
Przybilski
M
M
Schneider
M R
MR
Stahl
W
W
Tang
W
W
D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000494:pharmacology; D001853:Bone Marrow / Q000378:metabolism; D004337:Drug Carriers; D004967:Estrogens / Q000378:metabolism; D006801:Humans; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy*; D009607:Nitrosourea Compounds / Q000378:metabolism* / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000188:drug therapy; D011956:Receptors, Cell Surface / Q000378:metabolism*; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D004337:Drug Carriers; D004967:Estrogens; D009607:Nitrosourea Compounds; D011956:Receptors, Cell Surface