The role of polyamines in the prostate is unique among all tissues since in addition to synthesizing these molecules for cell growth, the gland produces massive quantities for export into semen. Perhaps relatedly, prostatic carcinoma xenografts have been shown to be sensitive to the antitumor activity of certain polyamine analogs. Herein we propose to develop a second generation of new polyamine analogs based on conformational restriction of structure. In addition. we propose to enhance their selectivity by conjugating analogs to a tetrapeptide sequence which confers substrate specificity for prostate specific antigen (PSA). These analogs and conjugates will be evaluated in several representative prostate carcinoma cell lines which differentially express PSA for their effects on cell growth and polyamine regulatory responses. Selected analogs will then be evaluated for their antitumor activity against human prostatic carcinoma xenografts growing in nude athymic mice. Our approach is supported by the clear therapeutic potential of recently observed findings in prostatic carcinoma cell lines the novel role of the prostate in polyamine production and export, and the recently attained clinical status of two polyamine analogs having structural and functional similarities to those proposed here.
Synthesis of polyamine analogs is proposed for use as potential therapies for prostatic cancer. While these efforts will initially focus on prostatic carcinoma, there exists the additional potential that the proposed analogs will find usefulness in the treatment of prostatic neoplasia, melanoma and large cell lung carcinoma as suggested by recent preclinical and clinical findings with other polyamine analogs. Thus, these studies are proposed as a prelude to a Phase II program in which selected analogs will be evaluated in other human tumor systems and where appropriate, advanced to clinical trial.
