The Kinetochore as Target for Cancer Drug Development

Due to diverse and complex genetic abnormalities in different cancers, there are no silver bullets in cancer treatment. According to the NCI (www.cancer.gov/), chemotherapy, together with radiotherapy and surgery, are the three major modalities of cancer treatment. As uncontrolled proliferation is the most distinctive characteristic of cancer cells, many anticancer drugs directly inhibit growth. These include drugs that target DNA or nucleotide metabolism and cell division. In a cell division cycle, mitosis is the phase during which duplicated sister chromatids physically separate from each other to produce two genetically identical daughter cells. Chemical compounds that interfere with this process should in principle be efficient inhibitors of cell proliferation. However, currently available anticancer drugs of this class are limited to two types of plant alkaloids: taxanes (docetaxel, paclitaxel) and vinca alkaloids (vinblastine, vincristine, vindesine, vinorelbine). The molecular target of these drugs is microtubules which form the spindle that is essential for accurate chromosome segregation. By interfering with proper formation of the spindle, these drugs interfere with the mitotic process that ultimately kills the cell (Wilson and Jordan, 1995). Although microtubule poisons are very efficient and are used extensively to treat cancer patients (especially those suffering from solid tumors), drug resistance is a serious problem (Orr et al., 2003; Jablonski et al., 2003). In an effort to overcome this problem, several structurally unrelated microtubule-targeted drugs are currently being tested in clinical trials (Rowinsky and Calvo, 2006). As these drugs target tubulin, a cytoskeleton protein involved not only inmitosis, but also in other important cellular functions outside of mitosis, the inhibition of all the microtubule functions in a patient produces dose-limiting toxicities such as peripheral neuropathy. This has stimulated the search for drugs that specifically target proteins that work exclusively in mitosis (Garber, 2005). As the