UCN 01, 17AAG, and XL844 are being tested in clinical trials, while the others are still in preclinical studies. UCN 01 NPI-2358 has been reported to promote apoptosis through G2 M checkpoint abrogation in various human cell lines. Thus, UCN 01 exerts more marked antitumor effects through combination with radio or chemotherapy . Results of three Phase I studies of combination therapy with UCN 01 in patients with solid tumors have been published, in which UCN 01 was combined with fluorouracil, topotecan, and cisplatin, respectively. UCN 01 plus topotecan or carboplatin were found to be generally well tolerated, however, combination of UCN 01 and fluorouracil did not show significant antitumor activity against advanced ovarian cancer .
Further research to develop these combinations BIBF1120 is warranted, especially focusing on reducing side effects. Aurora Kinase Inhibitors The evidence linking Aurora kinase overexpression and malignancy has stimulated interest in identifying and developing Aurora kinase inhibitors for cancer therapy. RNA interference targeting Aurora A has been found to suppress tumor growth and enhance sensitivity to chemotherapy and radiation induced apoptosis in human cells . Several Aurora kinase inhibitors, including VX 680, Hesperadin, ZM447439, AT 9283, MLN 8054, R 763, SU6668, and PHA 739358, have been identified and are undergoing phase I II clinical trials. One of these inhibitors, VX 680, the first Aurora kinase inhibitor to enter clinical trials, not only inhibits cell proliferation but also induces apoptosis in a wide spectrum of tumor types.
VX 680 was shown to greatly inhibit tumor growth in vivo in three xenograft models of leukemia, colon, and pancreatic tumors. It was reported that VX 680 has no effect on non cycling normal cells which makes it a promising anticancer agent. VX 680 also was found to be effective in reducing cell growth in different anaplastic thyroid cancer derived cell lines. In ovarian cancer, combination of VX 680 with docetaxel could significantly reduce cell proliferation and increase tumor cell apoptosis than VX 680 or docetaxel alone in vivo. Further investigation of this inhibitor is warranted to exploit its potential value in the treatment of cancer. In tobacco BY 2 cells, another Aurora kinase inhibitor, Hesperadin, was found to induce delayed transition from metaphase to anaphase and early exit from mitosis after chromosome segregation.
It is not clear, however, whether Hesperadin causes tumor cell death. In a colony formation assay, ZM447439, another Aurora kinase inhibitor, was found to be more toxic to proliferating cells than to nondividing cells, indicating that it might also be used selectively to kill proliferating tumor cells. ZM447439 is an effective apoptosis inducing and G2 M phase arresting agent in acute myeloid leukemia and Hep2 carcinoma cells. Inhibitors of Plk1 The G2 M phase regulator Plk1 is frequently overexpressed in cancers and correlates with aggressiveness and poor prognosis. Cogswell et al observed that silencing of Plk1 functions induced apoptosis accompanied by mitotic catastrophe in SAOS 2 and U 2OS tumor cells but not in normal human mammary epithelial cells. Findings from another study suggested that reduction of Plk1 expression via smal