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      Development of cell-cycle inhibitors for cancer therapy

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          Abstract

          The cell cycle governs the transition from quiescence through cell growth to proliferation. The key parts of the cell cycle machinery are the cyclin-dependent kinases ( cdks) and the regulatory proteins called cyclins. The cdks are rational targets for cancer therapy because their expression in cancer cells is often aberrant and their inhibition can induce cell death. Inhibitors of cdks can also block transcription.

          Several drugs targeting the cell cycle have entered clinical trials. These agents include flavopiridol, indisulam, AZD5438, SNS-032, bryostatin-1, seliciclib, PD 0332991, and SCH 727965. Phase i studies have demonstrated that these drugs can generally be administered safely. Phase ii studies have shown little single-agent activity in solid tumors, but combination studies with cytotoxic chemotherapy have been more promising. In hematologic malignancies, reports have shown encouraging single-agent and combination activity. Pharmacodynamic studies show that the dose and schedule of these drugs are crucial to permit maximum therapeutic effect.

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          Most cited references77

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          CDK inhibitors: positive and negative regulators of G1-phase progression.

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            A restriction point for control of normal animal cell proliferation.

            A B PARDEE (1974)
            This paper provides evidence that normal animal cells possess a unique regulatory mechanism to shift them between proliferative and quiescent states. Cells cease to increase in number under a diversity of suboptimal nutritional conditions, whereas a uniformity of metabolic changes follows these nutritional shifts. Evidence is given here that cells are put into the same quiescent state by each of these diverse blocks to proliferation and that cells escape at the same point in G(1) of the cell cycle when nutrition is restored. The name restriction point is proposed for the specific time in the cell cycle at which this critical release event occurs. The restriction point control is proposed to permit normal cells to retain viability by a shift to a minimal metabolism upon differentiation in vivo and in vitro when conditions are suboptimal for growth. Malignant cells are proposed to have lost their restriction point control. Hence, under very adverse conditions, as in the presence of antitumor agents, they stop randomly in their division cycle and die.
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              Cell cycle control and cancer.

              Multiple genetic changes occur during the evolution of normal cells into cancer cells. This evolution is facilitated in cancer cells by loss of fidelity in the processes that replicate, repair, and segregate the genome. Recent advances in our understanding of the cell cycle reveal how fidelity is normally achieved by the coordinated activity of cyclin-dependent kinases, checkpoint controls, and repair pathways and how this fidelity can be abrogated by specific genetic changes. These insights suggest molecular mechanisms for cellular transformation and may help to identify potential targets for improved cancer therapies.
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                Author and article information

                Journal
                Curr Oncol
                CO
                Current Oncology
                Multimed Inc. (66 Martin St. Milton, ON, Canada L9T 2R2 )
                1198-0052
                1718-7729
                March 2009
                : 16
                : 2
                : 36-43
                Affiliations
                [* ]Department of Medicine, Division of Solid Tumor Oncology, Melanoma and Sarcoma Service, and Laboratory of New Drug Development, Memorial Sloan–Kettering Cancer Center, New York, NY, U.S.A
                Author notes
                Correspondence to: Gary K. Schwartz, Memorial Sloan–Kettering Cancer Center, 1275 York Avenue, New York, New York 10021 U.S.A. E-mail: schwartg@ 123456mskcc.org
                Article
                co16-2-36
                10.3747/co.v16i2.428
                2669234
                19370178
                71905681-01a8-4a83-ad29-fd166e9c18af
                2009 Multimed Inc.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Categories
                Drug Development in Contemporary Oncology

                Oncology & Radiotherapy
                cyclins,cell cycle,phase ii clinical trials,cyclin-dependent kinases,phase i clinical trials

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