This study is a continuation of our investigations to identify and evaluate biological principles that may be useful in understanding and controlling prostate cancer. Our past studies have indicated that the Dunning R3327-H rat prostatic adenocarcinoma closely resembles human prostatic cancer in regards to its histology, slow growth rate, response to hormonal therapy by androgen ablation followed by an almost complete relapse to a hormone insensitive state, and its low response to standard chemotherapeutic agents. In the past we focused our attention on the causes of the relapse to the androgen-insensitive state and determined it was produced by tumor cell heterogeneity that was caused in part by genetic instability. The low response to the cancer chemotherapeutic agents was primarily caused by the low rate of cell proliferation which is very similar to that which exists in the human prostate cancer. In the process of these investigations, we determined that there were several types of androgen sensitivity that were characterized by differences between cell proliferation rates and cell death rates. The hormonal control of the two processes of cell proliferation and cell death varied separately in the different tumor lines. Furthermore, these two processes differed according to their level of endocrine stimulation. In the past more emphasis has been placed on the control of proliferation and comparatively little on what controls cell death. We propose to determine the biochemical changes that occur in the normal and cancerous prostate that regulate cell death in anticipation that this biological information may be useful in finding new directions of therapeutic control. This would be of particular interest in regulating slow growing cancers that have proven to be refractory to our standard therapeutic treatment that is usually directed to blocking proliferation. We have also shown that the shape of the nucleus in human prostatic cancer cells can be correlated with the aggressive nature of the tumors. It has been shown that this shape is determined by nuclear matrix that forms a structural scaffolding framework and organizes the DNA within the mammalian nucleus. We propose to study the biochemical changes occurring in the nuclear matrix and nucleus that differentiate between normal and cancerous cells. In these studies we will utilize 10 different lines of the Dunning prostatic tumors that have a wide range of growth, metastatic and therapeutic responses.
