The synthesis of 3H labelled steroid-nitrogen mustard derivatives and studies on their action in rat and human prostate.
Tissue receptor proteins are thought to be a key factor in selective retention and nuclear translocation of steroid hormones in their target tissues. Steroid-cytotoxic derivatives with high affinity for these receptor proteins may, therefore, be useful as site directed agents in the treatment of hormone dependent cancers. The prostatic retention and subcellular localisation of estramustine and a 17 beta nitrogen mustard derivative of 5 alpha-dihydrotestosterone have been compared since the latter compound has higher androgen receptor binding affinity than the former. The 5 alpha-dihydrotestosterone derivative was not retained more avidly than estramustine by either human or rat ventral prostatic tissue. Nuclear localisation could not be detected with either compound. The cytotoxic action of these compounds requires the liberation of the nitrogen mustard moiety. The cleavage rate of both compounds was low but similar in both benign and malignant prostatic tissues. We conclude that steroids are unlikely to be suitable agents for directing cytotoxic compounds to prostatic tissue particularly if the steroid-cytotoxic derivative requires metabolism for the expression of the cytotoxic activity.
D000818:Animals; D013196:Dihydrotestosterone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D004958:Estradiol / Q000378:metabolism; D004961:Estramustine / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D008297:Male; D009588:Nitrogen Mustard Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D011467:Prostate / Q000187:drug effects*; D051381:Rats; D011944:Receptors, Androgen / Q000378:metabolism; D013045:Species Specificity; D013739:Testosterone / Q000378:metabolism; D014018:Tissue Distribution
D009588:Nitrogen Mustard Compounds; D011944:Receptors, Androgen; D013196:Dihydrotestosterone; D004961:Estramustine; D013739:Testosterone; D004958:Estradiol; C035464:dihydrotestosterone-17-N-bis(2-chloroethyl)carbamate