The molecular pathways of polyamine catabolism in human breast cancer cell lines

The natural polyamines are essential for normal cell growth and differentiation. Breast cancer contains higher intracellular levels of the natural polyamines and exhibits altered activities of several of the enzymes involved in polyamine metabolism compared with normal breast tissue. Therefore, disruption of the polyamine metabolic pathway is a rational therapeutic target. One approach has been the development of polyamine analogues, which mimic the natural polyamines but have a modified function and, often, inhibit tumor cell proliferation. The induction of polyamine catabolism has been implicated in tumor cell response to specific polyamine analogues. This thesis evaluates the ability of a polyamine analogue, N1,N11-bis(ethyl)norspermine (BENSpm), to induce the polyamine catabolic enzymes spermidine/spermine N1-acetyltransferase (SSAT), N1-acetylpolyamine oxidase (PAO), and spermine oxidase (SMO(PAOh1)) in human breast cancer cell lines and examines their role in the overall response of breast cancer cell lines to BENSpm treatment. The results in this thesis suggest that SSAT and SMO(PAOh1) activities are the major mediators of the cellular response of breast cancer cells to exposure to BENSpm. These data also indicate that the role of the classical PAO may be less significant than previously thought with respect to polyamine homeostasis and the H2O2-mediated response to polyamine analogue exposure. The ability of BENSpm and another key polyamine analogue, CGC-11144, to synergize with standard chemotherapeutic agents in human breast cell lines was also assessed. BENSpm synergistically enhances the cytotoxic effects of two key chemotherapeutic agents, paclitaxel and 5-fluorouracil, in a schedule-dependent manner. Lastly, this thesis investigates the role that the polyamine catabolic enzymes play in this synergistic response. The results of this thesis suggest that the induction of SSAT and SMO(PAOh1) play a role in the synergistic antiproliferative effects of these combinations and provide evidence that combining standard chemotherapeutic agents with polyamine analogues that induce these enzymes is a rational approach to treating breast cancer. This study contributes to a better understanding of the role of polyamine catabolism in response to polyamine analogues in human breast cancer cell lines and aids in the design of more cytotoxic combination regimens to use in the treatment of human breast cancer.