Journal of Clinical Oncology, Vol 23, No 36 (December 20), 2005: pp. 9408-9421
© 2005 American Society of Clinical Oncology.
DOI: 10.1200/JCO.2005.01.5594
Targeting the Cell Cycle: A New Approach to Cancer Therapy
Gary K. Schwartz,
Manish A. Shah
From the Department of Medicine, Division of Solid Tumor Oncology, Gastrointestinal Oncology Service; and the Laboratory of New Drug Development, Memorial Sloan-Kettering Cancer Center, New York, NY
Address reprint requests to Gary K. Schwartz, MD, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021; e-mail: schwartg{at}mskcc.org
The cell cycle represents a series of tightly integrated events that allow the cell to grow and proliferate. Critical parts of the cell cycle machinery are the cyclin-dependent kinases (CDKs), which, when activated, provide a means for the cell to move from one phase of the cell cycle to the next. The CDKs are regulated positively by cyclins and regulated negatively by naturally occurring CDK inhibitors (CDKIs). Cancer represents a dysregulation of the cell cycle such that cells that overexpress cyclins or do not express the CDKIs continue to undergo unregulated cell growth. The cell cycle also serves to protect the cell from DNA damage. Thus, cell cycle arrest, in fact, represents a survival mechanism that provides the tumor cell the opportunity to repair its own damaged DNA. Thus, abrogation of cell cycle checkpoints, before DNA repair is complete, can activate the apoptotic cascade, leading to cell death. Now in clinical trials are a series of targeted agents that directly inhibit the CDKs, inhibit unrestricted cell growth, and induce growth arrest. Recent attention has also focused on these drugs as inhibitors of transcription. In addition, there are now agents that abrogate the cell cycle checkpoints at critical time points that make the tumor cell susceptible to apoptosis. An understanding of the cell cycle is critical to understanding how best to clinically develop these agents, both as single agents and in combination with chemotherapy.
Supported by National Cancer Institute (Bethesda, MD) Grant No. R01 CA 067819 (G.K.S.), and by the American Society of Clinical Oncology Young Investigator Award 2001 and the Cancer and Leukemia Group B Investigator Award 2001 (M.A.S.).
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
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