We propose to investigate the role of polyamine toxins as potential agents for the treatment of hormone refractory prostatic tumors. This proposal centers on the characterization of aziridinylputrescine which we have shown to be cytotoxic to hormone resistant prostatic cancer cells. We will radiolabel the aziridinyl putrescine to determine whether we are able to enhance its uptake to the same degree that we can enhance putrescines uptake in vivo, i.e. from 4:1 to 100:1. This selective enhancement suggests that we are able to target diamines to the prostate and prostatic tumors. We have observed that modification of one nitrogen, but not both nitrogens allows the amines utilization of the prostatic polyamine transporter. We will therefore synthesize and examine the toxicity of N- 1,N-1 dichloroethylputrescine towards prostatic tumors as well. As these are polyamine toxins and as intracellular modulation of polyamines is associated with altered cell growth, we will examine how these agents effect critical polyamine synthetic enzymes (ODC,SAMDC,SAT), their transcription (Northern analysis of mRNA), polyamine transport activity, polyamine modulated growth functions and cell death associated functions such as TRPM-2. We will evaluate means to enhance their toxic activities in vitro and in vivo against models of rodent and human androgen dependent, sensitive or insensitive tumor model systems. Prostatic cancer is the leading cause of cancer in the adult male. It is the second leading cause of death from cancer in the adult male. There is no treatment available for hormone refractory prostatic cancer. Our long range is to develop new methods to treat hormone resistant prostatic cancer.
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