Our long-range goal is to develop effective therapies for prostatic cancer. We have shown that aziridinyl putrescine (AZP) is toxic to prostatic cells. We propose to synthesize 3H-aziridinyl putrescine in order to determine its uptake, metabolism, and covalent binding to DNA, RNA and protein. We have shown that polyamine depletion by inhibitors of polyamine synthesis such as alpha-difluoromethylornithine reduces intracellular content of polyamines in the prostate and prostatic cell lines in vivo and in vitro. This is accompanied by an enhanced uptake of extracellular amines such as putrescine and AZP. The resultant increased uptake of AZP into the polyamine-depleted cell increases AZP's cytotoxic activity. Other manipulations have been shown to increase or decrease cellular uptake of polyamines and putrescine. Using cell growth assays, we will similarly determine whether these manipulations will increase or decrease the toxicity of AZP. AZP is an aziridine and potential alkylating agent. We will also examine the activity of biochemical response modifiers and other cytotoxic agents for their ability to enhance the toxicity of AZP. We will determine the uptake of AZP into R3327 slow-growing, well-differentiated Copenhagen rat prostatic tumor variants and human tumor xenographs in vitro. We will investigate those tumors with high AZP uptake to determine whether they will demonstrate a cytotoxic response to AZP in vivo. We will synthesize new cytotoxic derivatives of putrescine and determine whether these agents are similarly toxic to prostate cells. Prostatic cancer is the second major cause of cancer deaths in adult males in the United States. No effective forms of chemotherapy are available to treat this disease. Because of the high uptake of putrescine into prostatic tissue, it may be that cytotoxic putrescine derivatives offer a new avenue to approach the treatment of this disease.
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