Targeting hyperproliferative disorders with cyclin dependent kinase inhibitors

Abstract

Deregulated cell proliferation is associated with a variety of diseases including dysplasias and metaplasias of different tissues, psoriasis, atherosclerosis, restenosis after angioplastic surgery, and cancer [1-3]. Until recently, treatments for hyperproliferative disorders have revolved around chemical agents that kill actively dividing cells [4]. These agents include drugs that block DNA synthesis, such as DNA alkylators, topoisomerase, polymerase and nucleotide biosynthesis inhibitors. In addition, microtubule depolymerising and stabilising compounds have had widespread use as agents that interfere with Spindle function essential for chromosome segregation and the process of cell division. Over the last seven years, understanding the mechanism;regulating entry and exit, from the cell cycle has led to the identification of signal transduction, transcriptional and cell cycle regulatory pathways orchestrating cell proliferation. Abnormalities in these regulatory mechanisms have been implicated in a variety of hyperproliferative disorders, prompting the development of cyclin-dependent kinase(CDK) inhibitors as therapeutic agents [5-9]. Unlike drugs that are meant to kill actively dividing cells, CDK inhibitors can be used to re-establish order in the biochemical mechanisms governing a cell's decision to grow and divide - a departure from the traditional chemotherapeutic approach to the treatment of hyperproliferative disorders.