Cell cycle in vasculoproliferative diseases: potential interventions and routes of delivery.
Atherosclerosis and restenosis of epicardial vessels are among the greatest challenges facing the clinical cardiologist, and phenotypic modulation and proliferation of smooth muscle cells are major components of the vasculoproliferative response. Proliferation is regulated by the interplay of regulatory proteins at checkpoints in the cell cycle that alter cellular growth. Activation of the cell cycle and the genetic control of its progression are final common pathways in this process. Investigators have postulated that cell-cycle inhibition using drugs and genetic or physical methods has the potential to reverse or prevent the vasculoproliferative process. The current challenge is to translate in vitro data demonstrating the efficacy of cell-cycle inhibition to clinical trials. At present, the steps that must be taken to meet this goal are (1) to design methods of delivery of these agents to specific sites, (2) to identify appropriate cellular targets to elicit cell-cycle arrest, and (3) to improve the therapeutic ratio by minimizing potential side effects. This review discusses current concepts of the cell cycle, target-regulating mechanisms, and possible interventions in vasculoproliferative diseases. We also discuss ongoing clinical trials that use antiproliferative agents in the hope of limiting the course of these diseases, as well as the promise that antiproliferative therapy holds in the coming decade.
Sriram
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Division of Cardiology, University of Texas Medical Branch, Galveston, Texas, USA.
Patterson
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C
D000818:Animals; D042846:CDC2-CDC28 Kinases; D002453:Cell Cycle / Q000187:drug effects*; D018797:Cell Cycle Proteins / Q000187:drug effects / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects*; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000378:metabolism; D011687:Purines / Q000494:pharmacology; D014652:Vascular Diseases / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*
D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D011687:Purines; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; C109140:CVT 313