title: Development of more selective anti-cancer nitrosoureas.
abstract: 2-Chloroethyl-N-nitrosoureas are highly active anti-neoplastic drugs in clinical use for many years. Therapy with these DNA cross-linking agents is limited by their toxic side effects, cumulative and delayed bone marrow toxicity being the main dose-limiting one. Since the intrinsic anti-tumour activity of the nitrosourea group is very high, coupling to appropriate carrier molecules represents a challenge for target-orientated chemotherapy. Many human tumours contain receptors for steroid hormones. Therefore, 2-chloroethyl-N-nitroso-carbamoyl(CNC)-amino acid derivatives have been developed that are linked to steroid hormones. In the series of oestradiol (E2)-linked analogues CNC-L-alanine-E2-17-ester was significantly superior to other E2-linked congeners and to the unlinked equimolar mixture when tested against hormone-dependent N-methyl-N-nitrosourea-induced mammary carcinoma of the rat. Relevance of E2 receptor contents for therapy with E2-linked drugs is evidenced by loss of superiority of this analogue in hormone-independent mammary carcinomas. Some androgen-linked CNC-amino acids showed substantial affinity to the androgen receptor and in part also to the progesterone receptor. A preliminary study in rat leukaemia L5222 revealed the CNC-L-alanine-dihydrotestosterone-17-ester to be highly active. Studies with hormone-dependent tumour models are under way.
authors: University of Kaiserslautern, Department of Food Chemistry and Environmental Toxicology, FRG.
authors: G
authors: G
authors: Eisenbrand
authors: M R
authors: MR
authors: Berger
authors: J
authors: J
authors: Fischer
authors: M R
authors: MR
authors: Schneider
authors: W
authors: W
authors: Tang
authors: W J
authors: WJ
authors: Zeller
mesh_terms: D000728:Androgens / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D004958:Estradiol / Q000494:pharmacology; D009607:Nitrosourea Compounds / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D011987:Receptors, Steroid / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000728:Androgens; D000970:Antineoplastic Agents; D009607:Nitrosourea Compounds; D011987:Receptors, Steroid; D004958:Estradiol