Just as we have been successful in identifying a defect in repair of oxidative damage at the nuclear and mitochondrial levels of breast cancer cell lines, it is imperative that we also do so in prostate cancer, a commonly occurring malignancy that shares many features with breast cancer. Both have an age-adjusted incidence and death that are similar, both require gonads for development and can be treated by hormonal manipulation, both are also hormonally responsive, both have very similar life style risk factors (high animal fat diet, high red meat diet, high body mass, high birth weight, high dairy product intake) and both are significantly age related. Is there a role for oxidative damage and repair in disease imitation, promotion or progression that is tied to the frequency of oxidative DNA bases lesions in the genome and the efficiency of biologic pathways that recognize and remove this damage? The risk and host susceptibility factors involved in prostate cancer are poorly understood. The literature seems to suggest that defects in certain forms of DNA repair including oxidative damage repair may be critical in the development of prostate cancer. There is also evidence from the Grossman laboratory showing defective UV-damage repair in prostate cancer patients suggesting that there may be alterations in the nucleotide excision repair pathway as well. Research on the development of prostate cancer suggests that chronic and acute inflammation occurs in the prostate over the life span (e.g. prostatitis) and acts in synergy with environmental, genetic, and dietary factors to cause injury to prostatic epithelium. In response to this injury, cellular proliferation occurs (DeMarzo, Coffey, Nelson 1999). This proliferation occurs in a setting of oxidative stress related to the ongoing inflammatory process that in turn may result in high rates of oxidative damage to DNA (DeMarzo, Putzi, Nelson 2001). If this model is correct, we hypothesize that efficient base excision repair pathways may be critical for maintenance of genetic fidelity and ultimately prevention of cellular transformation. The accumulation of lesions within the DNA human prostate cancer specimens has been shown by Malins. Using GCMS technology he and his group have identified adducts in malignant and benign prostatic tissue. Further evidence supporting the hypothesis that the recognition and removal of oxidative base lesions (such as 8-oxo-G) may be pivotal in prostate carcinogenesis has been provided in work showing that sequence variation in the hOGG1 gene (that encodes a DNA glycosylase/AP lyase whose activity is the incision of 8-hydroxyguanine) may be associated with prostate cancer susceptibility (Isaacs 2002). Other findings that implicate a role for oxidative DNA damage include work by Oberley that has shown that SOD1, SOD2 and catalase levels were lower in prostate intraepithelial neoplasia and prostate cancer than in benign prostate epithelium (Cancer 2000). Finally, APE /ref-1 levels have also been shown to be dramatically elevated in prostate cancer (Kelley 2001). Taken together there is ample evidence to suggest the reactive oxygen species and perhaps oxidative DNA damage play a role in prostatic carcinogenesis. We have begun to evaluate whether oxidative DNA damage repair of 8-oxoG and other DNA base lesions are efficiently removed from nuclear and mitochondrial DNA. Using three well-studied prostate cancer cell lines, DU-145, LNCaP, and PC-3, we are examining the ability of nuclear and mitochondrial extracts prepared from these cell lines to incise a wide variety of commonly occurring oxidative DNA base lesions. The preliminary data suggest that untreated DU-145 and PC-3 cells have defects in the incision of 8-hydroxyguanine and thymine glycol adducts. Further experiments will include assays of other adducts (uracil, 5 hydroxycytocine, and AP sites), analysis of protein and mRNA levels of selected base excision repair enzymes and sequence analysis of implicated genes.
