Pharmacokinetics of Low Molecular Weight Heparin in Cancer Patients
Pharmacokinetics of Low Molecular Weight Heparin in Cancer Patients Compared to Patients With Unstable Angina Pectoris; The Possible Role of Heparanase
調査の概要
詳細な説明
Scientific background. The increased risk for venous thromboembolism (VTE) in cancer has long been recognized (1). Since first described by Trousseau in 1865, many aspects of this complex relationship are still obscure (2). Cancer patients have an increased risk for developing thrombosis. Similarly, patients presenting with idiopathic VTE are considered to have a higher risk of developing cancer (3). Approximately 10% of patients with idiopathic VTE harbor an underlying malignancy that can be detected by an extensive diagnostic work-up (4). Clinical data indicate that cancer alone is associated with a 4.1- fold risk of thrombosis, and chemotherapy increases the risk to 6.1- folds (5). Cancer patients develop postoperative VTE at least 2- folds more than patients without cancer undergoing the same surgical procedure (6). Treatment of VTE involves the administration of heparin, low molecular weight heparin (LMWH) or coumarin derivatives. Beside its anticoagulant effects, LMWH may also have an anti-tumoral effect (7-12). The use of LMWH relative to coumarin derivatives was associated with improved survival in patients with solid tumors who did not have metastatic disease at the time of an acute VTE (9). Moreover, addition of LMWH to chemotherapy increased survival of patients with small cell lung cancer (10).
Heparan sulfate proteoglycans (HSPGs) are ubiquitous macromolecules associated with the cell surface and extracellular matrix (ECM) of a wide range of cells of vertebrate and invertebrate tissues. Heparin is structurally related to heparan sulfate (HS), but has higher N- and O-sulfate contents (13). Mammalian endoglycosidase, capable of partially depolymerizing HS chains and commonly referred to as heparanase, has been identified in a variety of cell types and tissues, primarily cancer cells, activated cells of the immune system, platelets, and placenta (14-17). Heparanase is synthesized as a latent 65 kDa precursor whose activation involves proteolytic cleavage at two potential sites located at the N-terminal region of the molecule (Glu109 -Ser110 and Gln157 -lys158), resulting in the formation of two protein subunits that heterodimerize and form the active heparanase enzyme (18). Expression of heparanase correlates with the metastatic potential of human tumor cells (14-16, 19). Furthermore, elevated levels of heparanase were detected in the urine of some patients with aggressive metastatic disease (20). Heparin, LMWH, non-anticoagulant and chemically modified species of heparin (21, 22), as well as other polysaccharides (23, 24) which inhibit experimental metastasis, also inhibit tumor cell heparanase, while other related compounds had a small or no effect on both parameters (21-24). Recently, we demonstrated that the anticoagulant activities of heparin and LMWH can be neutralized by their pre-incubation with heparanase. Transgenic mice overexpressing heparanase, exhibited a hyper-coagulable phenotype expressed by a markedly shorter base-line APTT compared to control mice (25). These results may suggest that resistance to heparin, described in patients with malignancies (26, 27), could be attributed, in part, to high levels of heparanase often observed in cells (28, 29) and body fluids (20) of patients with an aggressive malignant disease. Degradation of heparin and LMWH by heparanase in vivo may be relevant in situations in which heparanase is over-expressed, and treatment with heparin or LMWH is needed (e.g., deep venous thrombosis in patients with pancreatic carcinoma) (29, 30). The pharmacokinetics of LMWH (i.e. the time course of absorption, distribution, metabolism, and degradation) as reflected by its effects upon factor Xa activity, was elucidated in several subgroups of patients (e.g. patients with renal failure, pregnant women…), but to the best of our knowledge was not addressed in patients with advanced solid tumors.
Objectives & expected significance. In view of the above described biological significance of the heparanase enzyme, and taking into account our recent in vitro and in vivo results (heparanase capability to cleave heparin and LMWH; and the altered coagulation profile in transgenic mice overexpressing heparanase) (25), we propose to focus on the following specific aims:
I) Measure plasma and urine heparanase levels in patients with advanced cancer suffering from VTE, and compare it to controls without cancer.
II) Elucidate the pharmacokinetics of LMWH in patients with advanced solid tumors (AST) suffering from VTE, and compare it to the pharmacokinetics of LMWH in patients with unstable angina pectoris.
III) Determine the correlation between heparanase blood levels and the pharmacokinetics of LMWH, if any.
References
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- Trousseau A: Phlegmasia alba dolens, in: Clinique Medicale de l'Hotel Dieu de Paris. Vol 3, ed 2. Balliere, Paris, 1865; pp 654-712.
- Valente M, Ponte E. Thrombosis and cancer. Minerva Cardioangiol. 2000; 48: 117-127.
- Prandoni P. Cancer and venous thromboembolism. Clinical implications of strong association. Pathophysiol Haemost Thromb. 2006; 35: 111-115.
- Heit JA, Silverstein MD, Mohr DN, Petterson TM, O'Fallon WM, Melton LJ 3rd. Risk factors for deep vein thrombosis and pulmonary embolism: a population-based case-control study. Arch Intern Med. 2000; 160: 809-815.
- Rickles FR, Levine MN. Epidemiology of thrombosis in cancer. Acta Haematol. 2001; 106: 6-12.
- von Tempelhoff GF, Harenberg J, Niemann F, Hommel G, Kirkpatrick CJ, Heilmann L. Effect of low molecular weight heparin (Certoparin) versus unfractionated heparin on cancer survival following breast and pelvic cancer surgery: A prospective randomized double-blind trial. Int J Oncol. 2000; 16: 815-824.
- Kakkar AK, Levine MN, Kadziola Z, Lemoine NR, Low V, Patel HK, Rustin G, Thomas M, Quigley M, Williamson RC. Low molecular weight heparin, therapy with dalteparin, and survival in advanced cancer: the fragmin advanced malignancy outcome study (FAMOUS). J Clin Oncol. 2004; 10: 1944-1948.
- Lee AY, Rickles FR, Julian JA, Gent M, Baker RI, Bowden C, Kakkar AK, Prins M, Levine MN. Randomized comparison of low molecular weight heparin and coumarin derivatives on the survival of patients with cancer and venous thromboembolism. J Clin Oncol. 2005; 23: 2123-2129.
- Altinbas M, Coskun HS, Er O, Ozkan M, Eser B, Unal A, Cetin M, Soyuer S. A randomized clinical trial of combination chemotherapy with and without low-molecular-weight heparin in small cell lung cancer. J Thromb Haemost. 2004; 2: 1266-1271.
- Klerk CP, Smorenburg SM, Otten HM, Lensing AW, Prins MH, Piovella F, Prandoni P, Bos MM, Richel DJ, van Tienhoven G, Buller HR. The effect of low molecular weight heparin on survival in patients with advanced malignancy. J Clin Oncol. 2005; 23: 2130-2135.
- Meyer G, Marjanovic Z, Valcke J, Lorcerie B, Gruel Y, Solal-Celigny P, Le Maignan C, Extra JM, Cottu P, Farge D. Comparison of low-molecular-weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer: a randomized controlled study. Arch Intern Med. 2002; 162:1729-1735.
- Casu B, Lindahl U. Structure and biological interactions of heparin and heparan sulfate. Adv Carbohydr Chem Biochem. 2001; 57: 159-206.
- Parish CR, Freeman C, Hulett MD. Heparanase: a key enzyme involved in cell invasion. Biochim Biophys Acta. 2001; 1471: M99-108.
- Vlodavsky I, Friedmann Y. Molecular properties and involvement of heparanase in cancer metastasis and angiogenesis. J Clin Invest. 2001; 108: 341-347.
- Nakajima M, Irimura T, Nicolson GL. Heparanases and tumor metastasis. J Cell Biochem. 1988; 36:157-167.
- Dempsey LA, Brunn GJ, Platt JL. Heparanase, a potential regulator of cell-matrix interactions. Trends Biochem Sci. 2000; 25: 349-351.
- Levy-Adam F, Miao HQ, Heinrikson RL, Vlodavsky I, Ilan N. Heterodimer formation is essential for heparanase enzymatic activity. Biochem Biophy Res Commun. 2003; 308: 885-891.
- Vlodavsky I, Friedmann Y, Elkin M, Aingorn H, Atzmon R, Ishai-Michaeli R, Bitan M, Pappo O, Peretz T, Michal I, Spector L, Pecker I. Mammalian heparanase: gene cloning, expression and function in tumor progression and metastasis. Nat Med. 1999; 5: 793-802.
- Shafat I, Zchria E, Nisman B, Nadir Y, Nakhoul F, Vlodavsky I, Ilan N. An ELISA method for the detection and quantification of human heparanase. Biochem Biophy Res Commun. 2006; 341: 958-963.
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- Parish CR, Coombe DR, Jakobsen KB, Bennett FA, Underwood PA. Evidence that sulphated polysaccharides inhibit tumour metastasis by blocking tumour-cell-derived heparanases. Int J Cancer. 1987; 40: 511-518.
- Parish CR, Freeman C, Brown KJ, Francis DJ, Cowden WB. Identification of sulfated oligosaccharide-based inhibitors of tumor growth and metastasis using novel in vitro assays for angiogenesis and heparanase activity. Cancer Res. 1999; 59: 3433-3441.
- Miao HQ, Elkin M, Aingorn E, Ishai-Michaeli R, Stein CA, Vlodavsky I. Inhibition of heparanase activity and tumor metastasis by laminarin sulfate and synthetic phosphorothioate oligodeoxynucleotides. Int J Cancer. 1999; 83: 424-431.
- Nasser NJ, Sarig G, Brenner B, Nevo E, Goldshmidt O, Zcharia E, Li JP, Vlodavsky I. Heparanase neutralizes the anticoagulation properties of heparin and low-molecular-weight heparin. J Thromb Haemost. 2006; 4: 560-565.
- Levy JH. Heparin resistance and antithrombin: should it still be called heparin resistance? Journal of cardiovascular anesthesia. 2004; 18: 129-130.
- Deitcher SR. Cancer and thrombosis: mechanisms and treatment. J Thromb Thrombolysis. 2003; 16: 21-31.
- Gohji K, Hirano H, Okamoto M, Kitazawa S, Toyoshima M, Dong J, Katsuoka Y, Nakajima M. Expression of three extracellular matrix degradative enzymes in bladder cancer. Int J Cancer. 2001; 95: 295-301.
- Koliopanos A, Friess H, Kleeff J, Shi X, Liao Q, Pecker I, Vlodavsky I, Zimmermann A, Buchler MW. Heparanase expression in primary and metastatic pancreatic cancer. Cancer Res. 2001; 61: 4655-59.
- Kim AW, Xu X, Hollinger EF, Gattuso P, Godellas CV, Prinz RA. Human heparanase-1 gene expression in pancreatic adenocarcinoma. J Gastrointest Surg. 2002; 6: 167-172.
研究の種類
入学 (実際)
連絡先と場所
研究場所
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Jerusalm、イスラエル、91031
- Shaare Zedek Medicla Center
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参加基準
適格基準
就学可能な年齢
健康ボランティアの受け入れ
受講資格のある性別
サンプリング方法
調査対象母集団
説明
Inclusion Criteria:
- Treatment with therapeutic dose of low molecular weight heparin
- Serum creatinine level < 1.5 mg/dl.
Exclusion Criteria:
- major surgery during the last month before investigation
- evidence of major infectious disease
研究計画
研究はどのように設計されていますか?
デザインの詳細
コホートと介入
グループ/コホート |
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1
A. Patients with pathologically or cytologically confirmed diagnosis of advanced solid malignancy. B. Venous thromboembolism: Deep vein thrombosis (DVT) confirmed by Doppler ultrasound, or pulmonary embolism confirmed by lung ventilation perfusion scan, or computerized tomography. C. Treatment with therapeutic dose of low molecular weight heparin. D. No major surgery during the last month before investigation. E. No evidence of major infectious disease. F. Serum creatinine level < 1.5 mg/dl. G. Informed consent |
2
A. Patients with unstable angina pectoris/ atypical chest pain, with no evidence of acute myocardial infarction. B. Treatment with therapeutic dose of low molecular weight heparin. C. No evidence of VTE. D. No major surgery during the last month before investigation. E. No evidence of major infectious disease. F. No history of malignancy. G. Serum creatinine level < 1.5 mg/dl. H. Informed consent |
この研究は何を測定していますか?
主要な結果の測定
結果測定 |
時間枠 |
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Pharmacokinetics of Low Molecular Weight Heparin (LMWH) in Cancer patients
時間枠:Interim analysis and at the end of the trial
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Interim analysis and at the end of the trial
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二次結果の測定
結果測定 |
時間枠 |
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The role of heparanase on the Pharmacokinetics of Low Molecular Weight Heparin (LMWH) in Cancer patients
時間枠:End of the study
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End of the study
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協力者と研究者
捜査官
- 主任研究者:Nicola j nasser, MD, PhD、Shaare Zedek Mc
出版物と役立つリンク
研究記録日
主要日程の研究
研究開始
一次修了 (実際)
研究の完了 (実際)
試験登録日
最初に提出
QC基準を満たした最初の提出物
最初の投稿 (見積もり)
学習記録の更新
投稿された最後の更新 (見積もり)
QC基準を満たした最後の更新が送信されました
最終確認日
詳しくは
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