Development of more selective anti-cancer nitrosoureas

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.