Markers predicting sensitivity to polyamine depletion in human breast cancer cell lines

Abstract: In spite of different treatment strategies today, breast cancer mortality is still high and new treatments are therefore needed. Potential new treatments can be found among the polyamine analogues. Polyamine analogues can be used in cancer treatment as cancer cells have a higher requirement for polyamines than the surrounding healthy tissue. Polyamines are flexible positive ions essential for the regulation of cell proliferation, differentiation and death. They are able to bind to vital negatively charged molecules in the cell, e.g. DNA, thereby affecting the structure of these macromolecules. In each cell, there is a pool of polyamines, which is highly controlled by biosynthesis, catabolism and transport in and out of the cell. Cellular polyamine deficiency is obtained by treating cells with substances such as polyamine analogues. When the cellular pool of polyamines is depleted, cell proliferation ceases and sometimes apoptosis is induced. The major aim of this study was to discover specific characteristics for polyamine deficiency sensitivity in human breast cancer cell lines, which could predict and determine their reaction to polyamine depletion. Since polyamine analogues are in clinical trials against cancer, markers for polyamine depletion sensitivity could be useful in predicting the outcome of cancer treatment using polyamine analogues. This thesis investigates several potential markers for cellular polyamine depletion sensitivity. The general conclusion of this work is that there are many different factors determining the cytotoxic reaction to treatment with a polyamine analogue, possibly working together. The polyamine metabolic enzymes SSAT and PAO, proteins involved in the regulation of apoptosis, Bcl 2 and pRb, and proteins involved in the Okazaki fragment maturation, DNA ligase I and FEN1, were found to affect polyamine analogue- induced cytotoxicity in human breast cancer cell lines. If tested cell lines prove to contain certain levels of these proteins there would be a greater chance of a successful treatment with polyamine analogues. In the future, several of these sensitivity markers could be used to determine if a cancer is susceptible to polyamine analogue treatment.