[Rapamycin: from the laboratory to the treatment of patients' arteries].
The history of rapamycin dates from 1965, when it was isolated from a microorganism in soil and its antibiotic properties were confirmed. Since its discovery, many scientific papers have demonstrated its antifungal and immunosuppressive properties. Our team pioneered in the study of the mechanism of action of rapamycin, motivated by its enormous promise as a therapeutic agent in atherosclerotic disease. We reported how it can inhibit the proliferation and migration of smooth muscle cells after a mechanical aggression, and demonstrated that this effect is mediated by p27 activation by rapamycin. The participation of p27, a key cyclin in the modulation of cell replication, in rapamycin's molecular signaling also spurred expectations in the field of oncological research because it involves a non-redundant system of regulation of the cell cycle susceptible to mutatio. The interesting characteristics of this active principle suggested that it would be worthwhile to investigate its protective effect in an experimental porcine model of angioplasty. Rapamycin showed that it can notably reduce vascular wall thickening, thus helping to preserve patency after angioplasty. Shortly after this study, the use of rapamycin-coated stents designed to release the active principle into the area of the atherosclerotic lesion was accompanied by an effective preservation of the arterial lumen in experimental models. It also produced a highly significant reduction in the rate of post-stent restenosis in various clinical studies in humans. However, the potential of this type of stent in diabetic patients is still unknown and we are on the point of beginning a large clinical trial (the FREEDOM study) to investigate its impact on the management of diabetic patients. Experimental and clinical evidence indicates that the development of oral agents capable of modifying the progression of atherosclerotic disease by acting on molecular targets involved in the control of the cell cycle will be a challenge in the coming years.
Fuster
Valentín
V
Mount Sinai Medical Center, New York, NY 10029-6574, United States.
D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy*; D003925:Diabetic Angiopathies / Q000188:drug therapy; D006801:Humans; D020123:Sirolimus / Q000627:therapeutic use*
D020123:Sirolimus