Grant: Operating Grant

The reductases are metabolic enzymes responsible for the regulation/control of various hormone pathways in the body. One of these is the regulation of testosterone and dihydrotestosterone concentrations, which play an important role in the development and progression of prostate cancer. This type of cancer will develop in one of seven men during their lifetime and one in twenty-seven will die as a result of this disease. These enzymes are also responsible for the breakdown/metabolism of drugs such as doxorubicin and daunorubicin which are commonly used in the treatment of breast cancer and leukemias. A potentially serious side effect with the use of these two anticancer drugs is chronic toxicity to the heart, which can be fatal in upwards of 30-50% of treated patients. Our research is examining the effect of genetic variation that exists from individual to individual in these enzyme pathways. We postulate that genetic variants in the testosterone and dihydrotestosterone metabolic pathways will result in increased concentrations of these two hormones which will result in the development or further progression of prostate cancer. This is particularly important for dihydrotestosterone. In a similar manner, if the elimination of doxorubicin or daunorubicin is decreased we postulate they will accumulate in the body and result in toxicity to the heart, which is a side effect seen with these two drugs in about 10% of treated patients. The goal of our research is to develop a clinical assay or diagnostic test to detect the presence of variants in the reductase enzymes that can be used as markers to predict the development of prostate cancer or anthracycline induced heart toxicity. Knowing the genetic make up of these enzyme pathways in patients will permit physicians to choose better therapies to significantly reduce mortality and morbidity in patients with these, and potentially other, types of cancer.