The Statins: Multifunctional Antithrombotic and Antineoplastic Drugs

ABSTRACT

Statins are approved by the Food and Drug Administration (FDA) for the treatment of hypercholesterolemia and have shown remarkable activity in preventing cardiovascular morbidity and mortality. The versatility of statins is increasingly being appreciated, however, and lowering cholesterol is only one attribute among many shared by this class of drugs. Most statins appear to have antithrombotic activity that is unrelated to the ability to reduce cholesterol levels, and several have significant antitumor effects. This article reviews the laboratory and clinical evidence that statins have antithrombotic and anticancer activity, discusses the ways in which these two activities intersect, and proposes novel uses for statins for the treatment of conditions other than hypercholesterolemia.

KEYWORDS

Statins - thrombosis - cancer

REFERENCES

• 1 Maron D, Fazio S, Linton M. Current perspectives on statins.  Circulation . 2000;  101 207-214
• 2 Kearney D, Fitzgerald D. The anti-thrombotic effects of statins.  J Am Coll Cardiol . 1999;  33 1305-1307
• 3 White C. Pharmacological effects of HMG Co A reductase inhibitors other than lipoprotein modulation.  J Clin Pharmacol . 1999;  39 111-118
• 4 Lefer A, Scalia R, Lefer D. Vascular effects of HMG CoA-reductase inhibitors (statins) unrelated to cholesterol lowering: new concepts for cardiovascular disease.  Cardiovasc Res . 2001;  49 281-287
• 5 Sotiriou C, Cheng J. Beneficial effects of statins in coronary artery disease-beyond lowering cholesterol.  Ann Pharmacother . 2000;  34 1432-1439
• 6 Corsini A. Fluvastatin: effects beyond cholesterol lowering.  J Cardiovasc Pharmacol Therapeut . 2000;  5 161-175
• 7 Bellosta S, Ferri N, Bernini F, Paoletti R, Corsini A. Non-lipid-related effects of statins.  Ann Med . 2000;  32 164-176
• 8 Rosenson R, Tangney C. Antiatherothrombotic properties of statins.  JAMA . 1998;  279 1643-1650
• 9 Koh K. Effects of statins on vascular wall: vasomotor function, inflammation and plaque stability.  Cardiovasc Res . 2000;  47 648-657
• 10 LaRosa J. Pleiotropic effects of statins and their clinical significance.  Am J Cardiol . 2001;  88 291-293
• 11 Shepherd J, Cobbe S, Ford I. et al . Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia.  N Engl J Med . 1995;  333 1301-1307
• 12 West of Scotland Coronary Prevention Study Group. Influence of pravastatin and plasma lipids on clinical events in the West of Scotland Coronary Prevention Study (WOSCOPS).  Circulation . 1998;  97 1440-1445
• 13 Anderson K, Wilson P, Odell P, Kannel W. An updated coronary risk profile.  Circulation . 1991;  83 357-363
• 14 Bucher H, Griffith L, Guyatt G. Effect of HMGcoA reductase inhibitors on stroke. A meta-analysis of randomized, controlled trials.  Ann Intern Med . 1998;  128 89-95
• 15 White H, Simes J, Anderson N. et al . Pravastatin therapy and the risk of stroke.  N Engl J Med . 2000;  343 317-326
• 16 Plehn J, Davis B, Sacks F. et al . Reduction of stroke incidence after myocardial infarction with pravastatin. The cholesterol and recurrent events (CARE) study.  Circulation . 1999;  99 216-223
• 17 Pedersen T, Kjekshus J, Pyorala K. et al . Effect of simvastatin on ischemic signs and symptoms in the Scandinavian simvastatin survival study (4S).  Am J Cardiol . 1998;  81 333-335
• 18 Hebert P, Gaziano J, Hennekens C. An overview of trials of cholesterol lowering and risk of stroke.  Arch Intern Med . 1995;  155 50-55
• 19 Ray J, Rosendaal F. The role of dyslipidemia and statins in venous thromboembolism.  Curr Control Trials Cardiovasc Med . 2001;  2 165-170
• 20 Grady D, Wenger N, Herrington D. et al . Postmenopausal hormone therapy increases risk for venous thromboembolic disease.  Ann Intern Med . 2000;  132 689-696
• 21 Ray J, Mamdani M, Tsuyuki R. et al . The use of statins and the subsequent development of deep vein thrombosis.  Arch Intern Med . 2001;  161 1405-1410
• 22 Hulley S, Grady D, Bush T. et al . Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group.  JAMA . 1998;  280 605-613
• 23 Ferro D, Basilli S, Alessandri C, Cara D, Violi F. Inhibition of tissue-factor-mediated thrombin generation by simvastatin.  Atherosclerosis . 2000;  149 111-116
• 24 Ferro D, Basili S, Alessandri C. et al . Simvastatin reduces monocyte-tissue-factor expression in type IIa hypercholesterolemia.  Lancet . 1997;  350 1222
• 25 Holschermann H, Hilgendorff A, Kemkes-Matthes B. et al . Simvastatin attenuates vascular hypercoagulability in cardiac transplant recipients.  Transplantation . 2000;  69 1830-1836
• 26 Undas A, Brummel K, Musial J, Mann K, Szczeklik A. Simvastatin depresses blood clotting by inhibiting activation of prothrombin, factor V, and factor XIII and by enhancing factor Va inactivation.  Circulation . 2001;  103 2248-2253
• 27 Szczeklik A, Musial J, Undas A. et al . Inhibition of thrombin generation by simvastatin and lack of additive effects of aspirin in patients with marked hypercholesterolemia.  J Am Coll Cardiol . 1999;  33 1286-1293
• 28 Joukhadar C, Klein N, Prinz M. et al . Similar effects of atorvastatin, simvastatin and pravastatin on thrombogenic and inflammatory parameters in patients with hypercholesterolemia.  Thromb Haemost . 2001;  85 47-51
• 29 Dangas G, Badimon J, Smith D. et al . Pravastatin therapy in hyperlipidemia: effects on thrombus formation and the systemic hemostatic profile.  J Am Coll Cardiol . 1999;  33 1294-1304
• 30 Dangas G, Smith D, Unger A. et al . Pravastatin: an antithrombotic effect independent of the cholesterol-lowering effect.  Thromb Haemost . 2000;  83 688-692
• 31 Aoki I, Aoki N, Kawano K. et al . Platelet-dependent thrombin generation in patients with hyperlipidemia.  J Am Coll Cardiol . 1997;  30 91-96
• 32 DiGarbo V, Bono M, DiRaimondo D. et al . Non lipid, dose-dependent effects of pravastatin treatment on hemostatic system and inflammatory response.  Eur J Clin Pharmacol . 2000;  56 277-280
• 33 Lacoste L, Lam J, Hung J. et al . Hyperlipidemia and coronary disease. Correction of the increased thrombogenic potential with cholesterol reduction.  Circulation . 1995;  92 3172-3177
• 34 Musial J, Undas A, Undas R, Brozek J, Szczeklik A. Treatment with simvastatin and low-dose aspirin depresses thrombin generation in patients with coronary heart disease and borderline-high cholesterol levels.  Thromb Haemost . 2001;  85 221-225
• 35 Wada H, Mori Y, Kaneko T. et al . Elevated plasma levels of vascular endothelial cell markers in patients with hypercholesterolemia.  Am J Hematol . 1993;  44 112-116
• 36 Dangas G, Smith D, Badimon J. et al . Gender differences in blood thrombogenicity in hyperlipidemic patients and response to pravastatin.  Am J Cardiol . 1999;  84 639-643
• 37 Colli S, Eligini S, Lalli M. et al . Vastatins inhibit tissue factor in cultured human macrophages: a novel mechanism of protection against atherothrombosis.  Arterioscler Thromb Vasc Biol . 1997;  17 265-272
• 38 Aikawa M, Rabkin E, Sugiyama S. et al . An HMG-CoA reductase inhibitor, cerivastatin, suppresses growth of macrophages expressing matrix metalloproteinases and tissue factor in vivo and in vitro.  Circulation . 2001;  103 276-283
• 39 Camera M, Toschi V, Comparato C. et al . Cholesterol-induced thrombogenicity of the vessel wall: inhibitory effect of fluvastatin.  Thromb Haemost . 2002;  87 748-755
• 40 Nurden P, Bihour C, Smith M, Raymond J, Nurden A. Platelet activation and thrombosis: studies in a patient with essential thrombocythemia.  Am J Hematol . 1996;  51 79-84
• 41 Wehmeier A, Sudhoff T, Meierkord F. Relation of platelet abnormalities to thrombosis and hemorrhage in chronic myeloproliferative disorders.  Semin Thromb Hemost . 1997;  23 391-402
• 42 van Genderen P, Leenknegt H, Michiels J. The paradox of bleeding and thrombosis in thrombocythemia: is von Willebrand factor the link?.  Semin Thromb Hemost . 1997;  23 385-389
• 43 Wehmeier A, Fricke S, Scharf R, Schneider W. A prospective study of haemostatic parameters in relation to the clinical course of myeloproliferative disorders.  Eur J Haematol . 1990;  45 191-197
• 44 Falanga A, Ofosu F, Cortelazzo S. et al . Hemostatic system activation in patients with lupus anticoagulant and essential thrombocythemia.  Semin Thromb Hemost . 1994;  20 324-327
• 45 Carvalho A, Ellman L. Activation of the coagulation system in polycythemia vera.  Blood . 1976;  47 669-678
• 46 Kornberg A, Rahimi-Levene N, Yona R, Mor A, Rachmilewitz E. Enhanced generation of monocyte tissue factor and increased plasma prothrombin fragment 1+2 levels in patients with polycythemia vera: mechanism of activation of blood coagulation.  Am J Hematol . 1997;  56 5-11
• 47 Lindmark E, Tenno T, Chen J, Siegbahn A. IL-10 inhibits LPS-induced human monocyte tissue factor expression in whole blood.  Br J Haematol . 1998;  102 597-604
• 48 Lopez S, Peiretti F, Bonardo B, Juhan-Vague I, Nalbone G. Effect of atorvastatin and fluvastatin on the expression of plasminogen activator inhibitor type-1 in cultured human endothelial cells.  Atherosclerosis . 2000;  152 359-366
• 49 Bourcier T, Libby P. HMG CoA reductase inhibitors reduce plasminogen activator inhibitor-1 expression by human vascular smooth muscle and endothelial cells.  Arterioscler Thromb Vasc Biol . 2000;  20 556-562
• 50 Wiesbauer F, Kaun C, Zorn G. et al . HMG CoA reductase inhibitors affect the fibrinolytic system of human vascular cells in vitro: a comparative study using different statins.  Br J Pharmacol . 2002;  135 284-292
• 51 Essig M, Nguyen G, Prie D. et al . 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors increase fibrinolytic activity in rat aortic endothelial cells. Role of geranylgeranylation and Rho proteins.  Circ Res . 1998;  83 683-690
• 52 Mussoni L, Banfi C, Sironi L, Arpaia M, Tremoli E. Fluvastatin inhibits basal and stimulated plasminogen activator inhibitor 1, but induces tissue type plasminogen activator in cultured human endothelial cells.  Thromb Haemost . 2000;  84 59-64
• 53 Isaacsohn J, Setaro J, Nicholas C. et al . Effects of lovastatin therapy on plasminogen activator inhibitor-1 antigen levels.  Am J Cardiol . 1994;  74 735-737
• 54 Cortellaro M, Cofrancesco E, Boschetti C. et al . Effects of fluvastatin and bezafibrate combination on plasma fibrinogen, t-plasminogen activator inhibitor and C reactive protein levels in coronary artery disease patients with mixed hyperlipidaemia (FACT study). Fluvastatin Alone and in Combination Treatment.  Thromb Haemost . 2000;  83 549-553
• 55 Bevilacqua M, Bettica P, Milani M. et al . Effect of fluvastatin on lipids and fibrinolysis in coronary artery disease.  Am J Cardiol . 1997;  79 84-87
• 56 Vigna G, Donega P, Passaro A. et al . Post-prandial effects of gemfibrozil vs simvastatin in hypercholesterolemic subjects with borderline hypertriglyceridemia.  Nutr Metab Cardiovasc Dis . 1999;  9 234-243
• 57 Fenton II J, Jeske W, Catalfamo J. et al . Statin drugs and dietary isoprenoids downregulate protein prenylation in signal transduction and are antithrombotic and prothrombolytic agents.  Bioschemistry (Mosc) . 2002;  67 85-91
• 58 Park H-J, Galper J. 3-Hydroxy-3-methylglutaryl CoA reductase inhibitors up-regulate transforming growth factor-β signaling in cultured heart cells via inhibition of geranylgeranylation of RhoA GTPase.  Proc Natl Acad Sci USA . 1999;  96 11525-11530
• 59 Essler M, Retzer M, Bauer M. et al . Stimulation of platelets and endothelial cells by mildly oxidized LDL proceeds through activation of lysophophatidic acid receptors and the Rho/Rho-kinase pathway. Inhibition by lovastatin.  Ann NY Acad Sci . 2000;  905 282-286
• 60 Aviram M, Hussein O, Rosenblat M. et al . Interactions of platelets, macrophages, and lipoproteins in hypercholesterolemia: antiatherogenic effects of HMG-CoA reductase inhibitor therapy.  J Cardiovasc Pharmacol . 1998;  31 39-45
• 61 Mayer J, Eller T, Brauer P. et al . Effects of long-term treatment with lovastatin on the clotting system and blood platelets.  Ann Hematol . 1992;  64 196-201
• 62 Hale L, Craver K, Berrier A. et al . Combination of fosinopril and pravastatin decreases platelet response to thrombin receptor agonist in monkeys.  Arterioscler Thromb Vasc Biol . 1998;  18 1643-1646
• 63 Schrör K, Lobel P, Steinhagen-Thiessen E. Simvastatin reduces platelet thromboxane formation and restores normal platelet sensitivity against prostacyclin in type IIa hypercholesterolemia.  Eicosanoids . 1989;  2 39-45
• 64 Ma L, Nie D, Hsu S. et al . Inhibition of platelet aggregation and expression of alpha granule membrane protein 140 and thromboxane B2 with pravastatin therapy for hypercholesterolemia.  J Assoc Acad Minor Phys . 2002;  13 23-26
• 65 Notarbartolo A, Davi G, Averna M. et al . Inhibition of thromboxane biosynthesis and platelet function by simvastatin in type IIa hypercholesterolemia.  Arterioscler Thromb Vasc Biol . 1995;  15 247-251
• 66 Huhle G, Abletshauser C, Mayer N. et al . Reduction of platelet activity markers in type II hypercholesterolemic patients by a HMG-CoA reductase inhibitor.  Thromb Res . 1999;  95 229-234
• 67 Kirk G, McLaren M, Muir A, Stonebridge P, Belch J. Decrease in P-selectin levels in patients with hypercholesterolaemia and peripheral arterial occlusive disease after lipid-lowering treatment.  Vasc Med . 1999;  4 23-26
• 68 Hochgraf E, Levy Y, Aviram M, Brook J, Cogan U. Lovastatin decreases plasma and platelet cholesterol levels and normalizes elevated platelet fluidity and aggregation in hypercholesterolemic patients.  Metabolism . 1994;  43 11-17
• 69 Osamah H, Mira R, Sorina S, Shlomo K, Michael A. Reduced platelet aggregation after fluvastatin therapy is associated with altered platelet lipid composition and drug binding to the platelets.  Br J Clin Pharmacol . 1997;  44 77-83
• 70 Tannous M, Cheung R, Vignini A, Mutus B. Atorvastatin increases ecNOS levels in human platelets of hyperlipidemic subjects.  Thromb Haemost . 1999;  82 1390-1394
• 71 Laufs U, Gertz K, Huang P. et al . Atorvastatin upregulates type III nitric oxide synthase in thrombocytes, decreases platelet activation, and protects from cerebral ischemia in normocholesterolemic mice.  Stroke . 2000;  31 2442-2449
• 72 Broijersen A, Eriksson M, Leijd B, Angelin B, Hjemdahl P. No influence of simvastatin treatment on platelet function in vivo in patients with hypercholesterolemia.  Arterioscler Thromb Vasc Biol . 1997;  1997 272-278
• 73 Broijersen A, Eriksson M, Larsson P. et al . Effects of selective LDL-apheresis and pravastatin therapy on platelet function in familial hypercholesterolaemia.  Eur J Clin Invest . 1994;  24 488-498
• 74 Chen H, Ikeda U, Shimpo M, Shimada K. Direct effects of statins on cells primarily involved in atherosclerosis.  Hypertens Res . 2000;  23 187-192
• 75 Anderson T, Gerhard M, Meredith I. et al . Systemic nature of endothelial dysfunction in atherosclerosis.  Am J Cardiol . 1995;  75 71B-74B
• 76 Quyyumi A, Dakak N, Mulcahy D. et al . Nitric oxide activity in the atherosclerotic human coronary circulation.  J Am Coll Cardiol . 1997;  29 308-317
• 77 Andrews N, Husain M, Dakak N, Quyyumi A. Platelet inhibitory effect of nitric oxide in the human coronary circulation: impact of endothelial dysfunction.  J Am Coll Cardiol . 2001;  37 510-516
• 78 Endres M, Laufs U, Huang Z. et al . Stroke protection by 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors mediated by endothelial nitric oxide synthase.  Proc Natl Acad Sci USA . 1998;  95 8880-8885
• 79 Alfon J, Guasch J, Berrozpe M, Badimon L. Nitric oxide synthase II (NOS II) gene expression correlates with atherosclerotic intimal thickening. Preventive effects of HMG-CoA reductase inhibitors.  Atherosclerosis . 1999;  145 325-331
• 80 Laufs U, Endres M, Custodis F. et al . Suppression of endothelial nitric oxide production after withdrawal of statin treatment is mediated by negative feedback regulation of rho GPTase gene transcription.  Circulation . 2000;  102 3104-3110
• 81 Wassmann S, Laufs U, Baumer A. et al . HMG-CoA reductase inhibitors improve endothelial cell dysfunction in normocholesterolemic hypertension via reduced production of reactive oxygen species.  Hypertension . 2001;  37 1450-1457
• 82 Marchesi S, Lupattelli G, Siepi D. et al . Short-term atorvastatin treatment improves endothelial function in hypercholesterolemic women.  J Cardiovasc Pharmacol . 2000;  36 617-621
• 83 Tsunekawa T, Hayashi T, Kano H. et al . Cerivastatin, a hydroxymethylglutaryl coenzyme A reductase inhibitor, improves endothelial function in elderly diabetic patients within 3 days.  Circulation . 2001;  104 376-379
• 84 Alonso R, Mata P, Andres R D. et al . Sustained long-term improvement of arterial endothelial function in heterozygous familial hypercholesterolemia patients treated with simvastatin.  Atherosclerosis . 2001;  157 423-429
• 85 Weis M, Pehlivanli S, Meiser B, Scheidt W V. Simvastatin treatment is associated with improvement in coronary endothelial function and decreased cytokine activation in patients after heart transplantation.  J Am Coll Cardiol . 2001;  38 814-818
• 86 Malik J, Melenovsky V, Wichterle D. et al . Both fenofibrate and atorvastatin improve vascular reactivity in combined hyperlipidaemia (fenofibrate versus atorvastatin trial-FAT).  Cardiovasc Res . 2001;  52 290-298
• 87 Guijarro C, Blanco-Colio L, Ortego M. et al . 3-Hydroxy-3-methylglutaryl coenzyme A reductase and isoprenylation inhibitors induce apoptosis of vascular smooth muscle cells in culture.  Circ Res . 1998;  83 490-500
• 88 Blanco-Colio L, Villa A, Ortego M. et al . 3-Hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitors, atorvastatin and simvastatin, induce apoptosis of vascular smooth muscle cells by down regulation of Bcl-2 expression and Rho A prenylation.  Atherosclerosis . 2002;  161 17-26
• 89 Laufs U, Marra D, Node K, Liao J. 3-Hydroxy-3-methylglutaryl-CoA reductase inhibitors attenuate vascular smooth muscle proliferation by preventing rho GTPase-induced down-regulation of p27 (Kip1).  J Biol Chem . 1999;  274 21926-21931
• 90 Libby P, Ridker P, Maseri A. Inflammation and atherosclerosis.  Circulation . 2002;  105 1135-1143
• 91 Pasceri V, Chang J, Willerson J, Yeh E. Modulation of C-reactive protein-mediated monocyte chemoattractant protein-1 in human endothelial cells by anti-atherosclerosis drugs.  Circulation . 2001;  103 2531-2534
• 92 Kothe H, Dalhoff K, Rupp J. et al . Hydroxymethylglutaryl coenzyme A reductase inhibitors modify the inflammatory response of human macrophages and endothelial cells infected with Chlamydia pneumoniae Circulation .  2000;  101 1760-1763
• 93 Bustos C, Hernandez-Presa M, Ortego M. et al . HMG-CoA reductase inhibition by atorvastatin reduces neointimal inflammation in a rabbit model of atherosclerosis.  J Am Coll Cardiol . 1998;  32 2057-2064
• 94 Sparrow C, Burton C, Hernandez M. et al . Simvastatin has anti-inflammatory and antiatherosclerotic activities independent of plasma cholesterol lowering.  Arterioscler Thromb Vasc Biol . 2001;  21 115-121
• 95 Phipps R. Atherosclerosis: the emerging role of inflammation and the CD40-CD40 ligand system.  Proc Natl Acad Sci USA . 2000;  97 6930-6932
• 96 Garlichs C, John S, Schmeisser A. et al . Upregulation of CD40 and CD40 ligand (CD154) in patients with moderate hypercholesterolemia.  Circulation . 2001;  104 2395-2400
• 97 Garlichs C, Eskafi S, Raaz D. et al . Patients with acute coronary syndromes express enhanced CD40 ligand/CD154 on platelets.  Heart . 2001;  86 649-655
• 98 Schonbeck U, Sukhova G, Shimizu K, Mach F, Libby P. Inhibition of CD40 signaling limits evolution of established atherosclerosis in mice.  Proc Natl Acad Sci USA . 2000;  97 7458-7463
• 99 Lutgens E, Cleutjens K, Heeneman S. et al . Both early and delayed anti-CD40L antibody treatment induces a stable plaque phenotype.  Proc Natl Acad Sci USA . 2000;  97 7464-7469
• 100 Ridker P, Rifai N, Pfeffer M, Sacks F, Braunwald E. Long-term effects of pravastatin on plasma concentration of C-reactive protein. The Cholesterol and Recurrent Events (CARE) investigators.  Circulation . 1999;  100 230-235
• 101 Ridker P, Rifai N, Clearfield M. et al . Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events.  N Engl J Med . 2001;  344 1959-1965
• 102 Albert M, Danielson E, Rifai N, Ridker P. Effect of statin therapy on C-reactive protein levels. The pravastatin inflammatio evaluation (PRINCE): a randomized trial and cohort study.  JAMA . 2001;  286 64-70
• 103 Goldstein J, Brown M. Regulation of the mevalonate pathway.  Nature . 1990;  343 425-430
• 104 Casey P, Solski P, Der C, Buss J. p21 ras is modified by the isoprenoid farnesol.  Proc Natl Acad Sci USA . 1989;  86 8323-8327
• 105 Bouterfa H, Sattelmeyer V, Czub S. et al . Inhibition of ras farnesylation by lovastatin leads to downregulation of proliferation and migration in primary cultured human gliobastoma cells.  Anticancer Res . 2000;  20 2761-2772
• 106 Khosravi-Far R, Cox A, Kato K, Der C. Protein prenylation: key to ras function and cancer intervention?.  Cell Growth Differ . 1992;  3 461-469
• 107 Newman T, Hulley S. Carcinogenicity of lipid-lowering drugs.  JAMA . 1996;  275 55-60
• 108 MacMahon S. Cholesterol reduction and death from non-coronary causes: evidence from randomised controlled trials.  Aust NZ J Med . 1994;  24 120-123
• 109 Hebert P, Gaziano J, Chan K, Hennekens C. Cholesterol lowering with statin drugs, risk of stroke and total mortality. An overview of randomized trials.  JAMA . 1997;  278 313-321
• 110 Bucher H, Griffith L, Guyatt G. Systematic review on the risk and benefit of different cholesterol-lowering interventions.  Arterioscler Thromb Vasc Biol . 1999;  19 187-195
• 111 Muldoon M, Manuck S, Mendelsohn A, Kaplan J, Belle S. Cholesterol reduction and non-illness mortality: meta-analysis of randomised clinical trials.  BMJ . 2001;  322 11-15
• 112 Bjerre L, LeLorier J. Do statins cause cancer?.  <~>A meta-analysis of randomized clinical trials. Am J Med . 2001;  110 716-723
• 113 Sacks F, Pfeffer M, Moye L. et al . The effect on coronary events after myocardial infarction in patients with average cholesterol levels.  N Engl J Med . 1996;  335 1001-1009
• 114 Downs J, Clearfield M, Weis S. et al . Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study.  JAMA . 1998;  279 1615-1622
• 115 Splichal J, Ornstein D, Hong-Dice Y, Downs J, Fischer J. Lovastatin for the prevention of melanoma: analysis of AFCAPS/TexCAPS (Abst).  Proc Am Soc Clin Oncol . 2001;  20 351a
• 116 Blais L, Desgagne A, LeLorier J. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors and the risk of cancer.  Arch Intern Med . 2000;  160 2363-2368
• 117 Fumagalli R. Occurence and significance of sterol precursors of cholesterol in human brain tumors.  J Neurochem . 1964;  11 561-565
• 118 Maltese W. 3-Hydroxy-3-methylglutaryl-coenzyme A reductase in human brain tumors.  Neurology . 1983;  33 1294-1299
• 119 Dimitroulakos J, Ye L, Benzaquen M. et al . Differential sensitivity of various pediatric cancers and squamous cell carcinomas to lovastatin-induced apoptosis: therapeutic implications.  Clin Cancer Res . 2001;  7 158-167
• 120 Lennernas H, Fager G. Pharmacodynamics and pharmacokinetics of the HMG-CoA reductase inhibitors: similarities and differences.  Clin Pharmacokinet . 1997;  232 403-425
• 121 Corsini A, Maggi F, Catapano A. Pharmacology of the competitive inhibitors of HMG-CoA reductase.  Pharmacol Res . 1995;  31 9-27
• 122 Wong W-L, Tan M, Xia Z. et al . Cerivastatin triggers tumor-specific apoptosis with higher efficacy than lovastatin.  Clin Cancer Res . 2001;  7 2067-2075
• 123 Xia Z, Tan M, Wong W. et al . Blocking protein geranylgeranylation is essential for lovastatin-induced apoptosis of human acute myeloid leukemia cells.  Leukemia . 2001;  15 1398-1407
• 124 Ohkanda J, Knowles D, Blaskovich M, Sebti S, Hamilton A. Inhibitors of protein farnesyltransferase as novel anticancer agents.  Curr Top Med Chem . 2002;  2 303-323
• 125 Rao S, Porter D, Chen X. et al . Lovastatin-mediated G1 arrest is through inhibition of the proteasome, independent of hydroxymethyl glutaryl-CoA reductase.  Proc Natl Acad Sci USA . 1999;  96 7797-7802
• 126 Baetta R, Paoletti R, Fuagalli R, Soma M. Mevalonate modulation of cell proliferation and apoptosis.  Oncol Rep . 1997;  4 257-261
• 127 Dimitroulakos J, Thai S, Wasfy G. et al . Lovastatin induces a pronounced differentiation response in acute myeloid leukemias.  Leuk Lymphoma . 2000;  40 167-178
• 128 Feleszko W, Balkowiec W, Sieberth E. et al . Lovastatin and tumor necrosis factor alpha exhibit potentiated antitumor effects against Ha-ras-transformed murine tumor via inhibition of tumor-induced angiogenesis.  Int J Cancer . 1999;  81 560-567
• 129 Mo H, Elson C. Apoptosis and cell-cycle arrest in human and murine tumor cells are initiated by isoprenoids.  J Nutr . 1999;  129 804-813
• 130 Perez-Sala D, Mollinedo F. Inhibition of isopenoid biosynthesis induces apoptosis in human promyelocytic HL-60 cells.  Biochem Biophys Res Commun . 1994;  199 1209-1215
• 131 Wojcik C, Bury M, Stoklosa T. et al . Lovastatin and simvastatin are modulators of the proteasome.  Int J Biochem Cell Biol . 2000;  32 957-965
• 132 Keyomarsi K, Sandoval L, Band V, Pardee A. Synchronization of tumor and normal cells from G1 to multiple cell cycles by lovastatin.  Cancer Res . 1991;  51 3602-3609
• 133 Nakasaki T, Wada H, Watanabe R. et al . Elevated tissue factor levels in leukemic cell homogenate.  Clin Appl Thromb Hemost . 2000;  6 14-17
• 134 Ornstein D, Meehan K, Zacharski L. The coagulation system as a target for the treatment of human gliomas.  Semin Thromb Hemost . 2002;  28 19-27
• 135 Zacharski L, Wojtukiewicz M, Costantini V, Ornstein D, Memoli V. Pathways of coagulation/fibrinolysis activation in malignancy.  Semin Thromb Hemost . 1992;  18 104-116
• 136 Zacharski L, Henderson W, Rickles F. et al . Effect of warfarin anticoagulation on survival in carcinoma of the lung, colon, head and neck and prostate.  Cancer . 1984;  53 2046-2052
• 137 Thornes R. Coumarins, melanoma and cellular immunity. In: McBrien D, Slator T, eds. Protective Agents in Cancer London: Academic Press 1983: 43-56
• 138 Ornstein D, Zacharski L. Treatment of cancer with anticoagulants: rationale in the treatment of melanoma.  Int J Hematol . 2001;  73 157-161
• 139 Thibault A, Samid D, Tompkins A. et al . Phase I study of lovastatin, an inhibitor of the mevalonate pathway, in patients with cancer.  Clin Cancer Res . 1996;  2 483-491
• 140 Larner J, Jane J, Laws E. et al . A phase I-II trial of lovastatin for anaplastic astrocytoma and glioblastoma multiforme.  Am J Clin Oncol . 1998;  21 579-583
• 141 Minden M, Dimitroulakos J, Nohynek D, Penn L. Lovastatin induced control of blast cell growth in an elderly patient with acute myeloblastic leukemia.  Leuk Lymphoma . 2001;  40 659-662
• 142 Soma M, Baetta R, Renzis M D. et al . In vivo enhanced antitumor activity of carmustine [N,N'-bis(2-chloroethyl)-N-nitrosourea] by simvastatin.  Cancer Res . 1995;  55 597-602
• 143 Feleszko W, Zagozdzon R, Golab J, Jakobisiak M. Potentiated antitumour effects of cisplatin and lovastatin against MmB16 melanoma in mice.  Eur J Cancer . 1998;  34 406-411