Uncontrolled proliferation is a common feature of malignant cells and the development of numerous molecules such as the retinoids (click here for our analysis of this field) has been aimed at this phenomenon. Proliferation correlates with a nuclear protein known as Ki-67, a molecule that accumulates from G1-phase to mitosis, where it is found at its highest content. Directly after mitosis the amount of the antigen decreases to a minimal level. During interphase the Ki-67 protein is predominantly associated with the nucleoli, whereas during mitosis it shows a close association with the chromosomes. Detailed cell cycle analysis revealed that the antigen is present in nuclei of proliferating (G1-,S-,G2-phase and mitosis) cells, but not in nuclei of quiescent or resting cells (G0-phase).



Recently it was demonstrated that the Ki-67 protein belongs to the family of MPM-2 antigens and that phosphorylation of the Ki-67 protein during mitosis is associated with the condensation of the chromosomes and the separation of sister chromatids. Furthermore, a C-terminal domain of Ki-67 protein (Kon21) is able to bind to all three members of the mammalian heterochromatin protein 1 (HP1) family in vitro and in vivo suggesting a role for Ki-67 protein in the control of higher order chromatin structure. We have recently addressed the subject of chromatin plasticity in our recent DiscoveryDossier “Histone deacetylase inhibitors: Redefining pharmaceutical approaches to the treatment of cancer” (Click here to access). In short this class of molecule, by modifying chromatin structure offers excellent opportunities for the control of many aspects of tumor progression including hyperproliferation. Likewise targeting Ki-67 may also offer considerable therapeutic opportunities.



In a recent study researchers from the Universities of Iowa and Lübeck determined the ability of a phosphorothioate antisense oligodeoxyribonucleotide (ODN) targeted against the Ki-67 mRNA to specifically inhibit tumor cell proliferation in cell culture, in multicellular three-dimensional spheroids (MCS) and in subcutaneous murine tumor models. Antisense treatment of one myeloid and different epithelial tumor cell lines in suspension and monolayer culture, respectively, resulted in specific reduction of the Ki-67 mRNA and protein, inhibition of proliferation and increased apoptotic cell death. Multicellular human bladder carcinoma spheroids lost their three-dimensional structure and underwent cell-death after incubation with antisense oligonucleotides. The growth of subcutaneous syngeneic prostatic and transitional cell tumors in immunocompetent mice was significantly inhibited in antisense-treated animals. From these findings it can be concluded that antisense inhibition of Ki-67 protein expression may be a rational approach in anticancer therapy.

Adapted from Kausch et al et al, Int J Cancer 2003 Jul 10;105(5):710-6

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