Imatinib and Hyperlipidemia
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《新英格兰医药杂志》
To the Editor: We report on a series of nine patients with hyperlipidemia and either chronic myeloid leukemia or the hypereosinophilic syndrome, in eight of whom plasma lipid levels normalized within one month after imatinib therapy (at a dose of 400 mg daily) was started. All nine patients had hypercholesterolemia (mean plasma total cholesterol level, 254 mg per deciliter; range, 223 to 293); four of them also had hypertriglyceridemia (mean plasma triglyceride level, 264 mg per deciliter; range, 230 to 368). Patients who had concomitant diabetes mellitus, were currently consuming alcohol, or were using oral contraception were excluded. Diet, weight, and levels of physical activity remained unchanged during the course of imatinib therapy. No patient received any drug known to affect lipid metabolism. The normalization (estimated to occur 30 days after imatinib was started) of cholesterolemia in eight of the nine patients (mean plasma total cholesterol level, 176 mg per deciliter; range, 160 to 187) and of triglyceridemia in three of four patients (mean plasma triglyceride level, 130 mg per deciliter; range, 126 to 138) was persistent and long-lasting (median follow-up, 20 months; range, 4 to 30). Both hypercholesterolemia and hypertriglyceridemia were unmodified in the one patient whose condition did not respond to the therapy (Table 1).
Table 1. Plasma Lipid Levels in Nine Patients Receiving Imatinib Therapy.
Imatinib mesylate (formerly STI571; now Gleevec in the UnitedStates and Glivec in Europe ) is a small molecule that has been shown to have potent inhibitory activity against several tyrosine kinases, including ABL, c-Kit, and the platelet-derived growth factor receptor (PDGFR), and has become the primary target of therapy in chronic myeloid leukemia, gastrointestinal stromal tumors, and the hypereosinophilic syndrome, respectively.1 Tyrosine kinases are likely to play a pivotal role in the pathogenesis of several diseases. In particular, PDGFR binds specifically to and phosphorylates the cytoplasmic tail of the low-density lipoprotein (LDL)-receptor–related protein (LRP),2 a member of the LDL-receptor superfamily, which is known to act in areas as diverse as the degradation of proteases, the activation of lysosomal enzymes, cholesterol metabolism, and glucose-induced insulin secretion.3
Increasing evidence suggests that LRP is involved in cellular signaling in a phosphorylation-dependent manner. Inhibition by imatinib of PDGFR-dependent phosphorylation of the cytoplasmic domain of LRP has been shown to prevent intimal hyperplasia after vascular injuries and fibrovascular proliferation in mice with hypercholesterolemia.4 Moreover, imatinib has been shown to delay the development of atherosclerosis and nephropathy in experimental models, especially in the context of diabetes, and in vivo, to induce the regression of type 2 diabetes mellitus.5 Our observations suggest that in vivo modulation of the phosphorylation pathway with the use of tyrosine kinase inhibitors may result in modifications to lipoprotein metabolism that might be useful in the prevention of atherosclerosis.
Michele Gottardi, M.D.
Ca' Foncello Hospital
31100 Treviso, Italy
michelegottardi@hotmail.com
Enzo Manzato, M.D.
University of Padua
35128 Padua, Italy
Filippo Gherlinzoni, M.D.
Ca' Foncello Hospital
31100 Treviso, Italy
References
Krause DS, Van Etten RA. Tyrosine kinases as targets for cancer therapy. N Engl J Med 2005;353:172-187.
Loukinova E, Ranganathan S, Kuznetsov S, et al. Platelet-derived growth factor (PDGF)-induced tyrosine phosphorylation of the low density lipoprotein receptor-related protein (LRP): evidence for integrated co-receptor function between LRP and the PDGF. J Biol Chem 2002;277:15499-15506.
Fujino T, Asaba H, Kang MJ, et al. Low-density lipoprotein receptor-related protein 5 (LRP5) is essential for normal cholesterol metabolism and glucose-induced insulin secretion. Proc Natl Acad Sci U S A 2003;100:229-234.
Boucher P, Gotthardt M, Li WP, Anderson RG, Herz J. LRP: role in vascular wall integrity and protection from atherosclerosis. Science 2003;300:329-332.
Veneri D, Franchini M, Bonora E. Imatinib and regression of type 2 diabetes. N Engl J Med 2005;352:1049-1050.
Table 1. Plasma Lipid Levels in Nine Patients Receiving Imatinib Therapy.
Imatinib mesylate (formerly STI571; now Gleevec in the UnitedStates and Glivec in Europe ) is a small molecule that has been shown to have potent inhibitory activity against several tyrosine kinases, including ABL, c-Kit, and the platelet-derived growth factor receptor (PDGFR), and has become the primary target of therapy in chronic myeloid leukemia, gastrointestinal stromal tumors, and the hypereosinophilic syndrome, respectively.1 Tyrosine kinases are likely to play a pivotal role in the pathogenesis of several diseases. In particular, PDGFR binds specifically to and phosphorylates the cytoplasmic tail of the low-density lipoprotein (LDL)-receptor–related protein (LRP),2 a member of the LDL-receptor superfamily, which is known to act in areas as diverse as the degradation of proteases, the activation of lysosomal enzymes, cholesterol metabolism, and glucose-induced insulin secretion.3
Increasing evidence suggests that LRP is involved in cellular signaling in a phosphorylation-dependent manner. Inhibition by imatinib of PDGFR-dependent phosphorylation of the cytoplasmic domain of LRP has been shown to prevent intimal hyperplasia after vascular injuries and fibrovascular proliferation in mice with hypercholesterolemia.4 Moreover, imatinib has been shown to delay the development of atherosclerosis and nephropathy in experimental models, especially in the context of diabetes, and in vivo, to induce the regression of type 2 diabetes mellitus.5 Our observations suggest that in vivo modulation of the phosphorylation pathway with the use of tyrosine kinase inhibitors may result in modifications to lipoprotein metabolism that might be useful in the prevention of atherosclerosis.
Michele Gottardi, M.D.
Ca' Foncello Hospital
31100 Treviso, Italy
michelegottardi@hotmail.com
Enzo Manzato, M.D.
University of Padua
35128 Padua, Italy
Filippo Gherlinzoni, M.D.
Ca' Foncello Hospital
31100 Treviso, Italy
References
Krause DS, Van Etten RA. Tyrosine kinases as targets for cancer therapy. N Engl J Med 2005;353:172-187.
Loukinova E, Ranganathan S, Kuznetsov S, et al. Platelet-derived growth factor (PDGF)-induced tyrosine phosphorylation of the low density lipoprotein receptor-related protein (LRP): evidence for integrated co-receptor function between LRP and the PDGF. J Biol Chem 2002;277:15499-15506.
Fujino T, Asaba H, Kang MJ, et al. Low-density lipoprotein receptor-related protein 5 (LRP5) is essential for normal cholesterol metabolism and glucose-induced insulin secretion. Proc Natl Acad Sci U S A 2003;100:229-234.
Boucher P, Gotthardt M, Li WP, Anderson RG, Herz J. LRP: role in vascular wall integrity and protection from atherosclerosis. Science 2003;300:329-332.
Veneri D, Franchini M, Bonora E. Imatinib and regression of type 2 diabetes. N Engl J Med 2005;352:1049-1050.