Perspectives on cancer therapy: cell cycle blockers and perturbators

Over the past few decades, remarkable advances have been achieved in cancer therapy, including chemotherapeutic agents, their mode of application and more broader therapeutic strategies. Promising new therapeutic targets have emerged in the past ten years as a result of recent advances in our understanding of the pathobiology of malignant cells, in particular, regarding functions of suppressor oncogene products. Among them, the agents that alter the cell cycle have recently been of particular interest, since cell cycle regulation is basic mechanism underlying cell fate, i.e., proliferation, differentiation or death. Furthermore, the human genome project has made possible the future development of so-called "tailor-made medicine", i.e. the design of appropriate drugs for specific genetic profiles and application of drugs that are tailored to each tumor and patient. In this article, we will introduce and discuss recent progress in the development of agents that influence the cell cycle and their future potential in cancer therapy from three standpoints with our own experimental works; i) the inhibition of cell proliferation and/or induction of differentiation by cyclin-dependent kinase (cdk)-inhibitor, e.g. olomoucin, butyrolactone-I, ii) induction of apoptosis by directing "abortive cell cycle", or the transient upregulation of cdk activity, e.g. flavopiridol, and iii) countering the development of drug resistance by adjunctive administration of cdk-inhibitors with conventional anti-cancer drug, e.g., p21-gene transfer with cisplatin. Conclusively none of these three approaches by itself is satisfactory, and that the effective cancer therapies will require the administration of several agents and/or methods under the design of their synergistic effects.