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H. S. Friedman - One of the best experts on this subject based on the ideXlab platform.
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Tinzaparin prophylaxis against venous thromboembolic complications in brain tumor patients
Journal of neuro-oncology, 2009Co-Authors: Stephanie L. Perry, D. A. Reardon, A. Desjardins, H. S. Friedman, Cindy Bohlin, A. H. Friedman, J. J. VredenburghAbstract:The purpose of this study was to determine the safety of Tinzaparin for deep vein thrombosis prophylaxis in newly diagnosed grade III–IV malignant glioma patients. Patients were initiated on daily Tinzaparin at a fixed dose of 4,500 IU subcutaneously between 48 h and 4 weeks post-operative for planned duration of 12 months. During chemotherapy cycles, blood counts were monitored weekly and Tinzaparin was held if the platelet count decreased to 100,000. Forty patients were enrolled into the study, 35 with glioblastoma multiforme and 5 with anaplastic astrocytoma. Possible attributable toxicity was limited to two patients who developed CNS hemorrhages (one grade 1 and one grade 2) and one patient with an increase in liver enzymes (grade 3). There were no patients with a grade 4 or 5 CNS hemorrhages or systemic hemorrhages ≥grade 2. The median time on prophylactic Tinzaparin was 161 days (range of 5 to 601 days). One patient developed a deep venous thrombosis while taking Tinzaparin, and three patients developed thromboembolic complications while off Tinzaparin. Tinzaparin at a fixed prophylactic dose is safe and may decrease the incidence of thromboembolic complications in brain tumor patients.
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Tinzaparin prophylaxis in brain tumor patients
Journal of Clinical Oncology, 2007Co-Authors: C. W. Bohlin, D. A. Reardon, A. Desjardins, J. A. Quinn, J. N. Rich, D. A. Bota, K. Goli, H. S. Friedman, J. J. VredenburghAbstract:12506 Background: Thromboembolic disease is the second leading cause of death in brain tumor patients. Various studies have documented a 20–40% risk of deep vein thrombosis and / or pulmonary embolus in brain tumor patients. When used as prophylaxis, Tinzaparin, a low molecular weight heparin with factor Xa activity, has a low complication rate and low incidence of bleeding complications. With the anticipated benefit exceeding any risk, prophylaxis with Tinzaparin may be safe and effective. Methods: A phase II trial of prophylactic Tinzaparin for newly diagnosed brain tumor patients has completed accrual at 40 patients. A fixed daily dose of 4500 IU subcutaneous Tinzaparin was given beginning a minimum of 48 hours post-operatively and a maximum of 4 weeks post-operatively. Patients consented to take Tinzaparin daily for 12 months. Weekly blood counts were monitored during chemotherapy cycles. Tinzaparin was held if platelet count was <50,000 and resumed once the platelets were >100,000. Tinzaparin was discontinued in patients who began treatment with avastin. Results: Of 40 patients, 7 remain on treatment. Patients have taken Tinzaparin for 4–52 weeks with a median of 21 weeks. One of the patients developed a grade 3 CNS hemorrhage and one had a grade 1 CNS hemorrhage, necessitating cessation of the Tinzaparin, there have been no grade 4 or 5 CNS hemorrhages or treatment associated mortality. No patients developed = grade 2 systemic hemorrhages. One patient developed a deep venous thrombosis while taking Tinzaparin, and three patients developed thromboembolic complications while off Tinzaparin secondary to thrombocytopenia. One patient was taken off study for increased liver function tests, possibly secondary to Tinzaparin. Conclusions: Thus far, daily prophylactic Tinzaparin has proven safe and effective in decreasing the incidence of thromboembolic disease in brain tumor patients. We plan a phase III study upon the safe completion of the last 7 patients on this phase II study. No significant financial relationships to disclose.
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Tinzaparin prophylaxis against thromboembolic complications in brain tumor patients
Journal of Clinical Oncology, 2006Co-Authors: J. J. Vredenburgh, D. A. Reardon, A. Desjardins, J. A. Quinn, J. N. Rich, Cindy Bohlin, Sith Sathornsumetee, Lawrence B. Marks, A. H. Friedman, H. S. FriedmanAbstract:1539 Background: Thromboembolic complications are common in brain tumor patients, contribute to the morbidity and mortality and complicate treatment. Twenty to 40% of brain tumor patients develop a deep venous thrombosis and/or pulmonary embolus during their course. Thromboembolic complications are the second leading cause of death in brain tumor patients. One of the low molecular weight heparins, Tinzaparin, has increased factor Xa activity as opposed to thrombin inhibition, which may improve the therapeutic:toxicity ratio. Methods: We report a phase II trial of prophylactic Tinzaparin for newly diagnosed brain tumor patients. Twenty-seven of the planned 40 patients have been accrued. Patients received daily Tinzaparin at a fixed dose of 4500 IU subcutaneously beginning a minimum of 48 hours post-operatively and a maximum of 4 weeks post-operatively. Patients were scheduled to receive Tinzaparin for 12 months. During chemotherapy cycles, the blood counts were monitored weekly. If the platelet count was <50,000, the Tinzaparin was held until the platelets were >100,000. Results: One of the patients developed a grade 3 CNS hemorrhage, necessitating cessation of the Tinzaparin, there have been no grade 4 or 5 CNS hemorrhages or treatment associated mortality. Also, there have been no ≥ grade 2 systemic hemorrhages. One patient developed a deep venous thrombosis while taking Tinzaparin, and three patients developed thromboembolic complications while off Tinzaparin secondary to thrombocytopenia. One patient was taken off study for increased liver function tests, possibly secondary to Tinzaparin. The patients have taken the Tinzaparin for 4–52 weeks, with a median of 18 weeks. Conclusions: Tinzaparin at a fixed prophylactic dose is safe and may decrease the incidence of thromboembolic complications in brain tumor patients. If the completed phase II study yields similar results, a phase III trial is warranted. No significant financial relationships to disclose.
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Tinzaparin prophylaxis against thromboembolic complications in brain tumor patients
Journal of Clinical Oncology, 2006Co-Authors: J. J. Vredenburgh, D. A. Reardon, A. Desjardins, J. A. Quinn, J. N. Rich, Cindy Bohlin, Sith Sathornsumetee, Lawrence B. Marks, A. H. Friedman, H. S. FriedmanAbstract:1539 Background: Thromboembolic complications are common in brain tumor patients, contribute to the morbidity and mortality and complicate treatment. Twenty to 40% of brain tumor patients develop a deep venous thrombosis and/or pulmonary embolus during their course. Thromboembolic complications are the second leading cause of death in brain tumor patients. One of the low molecular weight heparins, Tinzaparin, has increased factor Xa activity as opposed to thrombin inhibition, which may improve the therapeutic:toxicity ratio. Methods: We report a phase II trial of prophylactic Tinzaparin for newly diagnosed brain tumor patients. Twenty-seven of the planned 40 patients have been accrued. Patients received daily Tinzaparin at a fixed dose of 4500 IU subcutaneously beginning a minimum of 48 hours post-operatively and a maximum of 4 weeks post-operatively. Patients were scheduled to receive Tinzaparin for 12 months. During chemotherapy cycles, the blood counts were monitored weekly. If the platelet count was <...
J. J. Vredenburgh - One of the best experts on this subject based on the ideXlab platform.
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Tinzaparin prophylaxis against venous thromboembolic complications in brain tumor patients
Journal of neuro-oncology, 2009Co-Authors: Stephanie L. Perry, D. A. Reardon, A. Desjardins, H. S. Friedman, Cindy Bohlin, A. H. Friedman, J. J. VredenburghAbstract:The purpose of this study was to determine the safety of Tinzaparin for deep vein thrombosis prophylaxis in newly diagnosed grade III–IV malignant glioma patients. Patients were initiated on daily Tinzaparin at a fixed dose of 4,500 IU subcutaneously between 48 h and 4 weeks post-operative for planned duration of 12 months. During chemotherapy cycles, blood counts were monitored weekly and Tinzaparin was held if the platelet count decreased to 100,000. Forty patients were enrolled into the study, 35 with glioblastoma multiforme and 5 with anaplastic astrocytoma. Possible attributable toxicity was limited to two patients who developed CNS hemorrhages (one grade 1 and one grade 2) and one patient with an increase in liver enzymes (grade 3). There were no patients with a grade 4 or 5 CNS hemorrhages or systemic hemorrhages ≥grade 2. The median time on prophylactic Tinzaparin was 161 days (range of 5 to 601 days). One patient developed a deep venous thrombosis while taking Tinzaparin, and three patients developed thromboembolic complications while off Tinzaparin. Tinzaparin at a fixed prophylactic dose is safe and may decrease the incidence of thromboembolic complications in brain tumor patients.
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Tinzaparin prophylaxis in brain tumor patients
Journal of Clinical Oncology, 2007Co-Authors: C. W. Bohlin, D. A. Reardon, A. Desjardins, J. A. Quinn, J. N. Rich, D. A. Bota, K. Goli, H. S. Friedman, J. J. VredenburghAbstract:12506 Background: Thromboembolic disease is the second leading cause of death in brain tumor patients. Various studies have documented a 20–40% risk of deep vein thrombosis and / or pulmonary embolus in brain tumor patients. When used as prophylaxis, Tinzaparin, a low molecular weight heparin with factor Xa activity, has a low complication rate and low incidence of bleeding complications. With the anticipated benefit exceeding any risk, prophylaxis with Tinzaparin may be safe and effective. Methods: A phase II trial of prophylactic Tinzaparin for newly diagnosed brain tumor patients has completed accrual at 40 patients. A fixed daily dose of 4500 IU subcutaneous Tinzaparin was given beginning a minimum of 48 hours post-operatively and a maximum of 4 weeks post-operatively. Patients consented to take Tinzaparin daily for 12 months. Weekly blood counts were monitored during chemotherapy cycles. Tinzaparin was held if platelet count was <50,000 and resumed once the platelets were >100,000. Tinzaparin was discontinued in patients who began treatment with avastin. Results: Of 40 patients, 7 remain on treatment. Patients have taken Tinzaparin for 4–52 weeks with a median of 21 weeks. One of the patients developed a grade 3 CNS hemorrhage and one had a grade 1 CNS hemorrhage, necessitating cessation of the Tinzaparin, there have been no grade 4 or 5 CNS hemorrhages or treatment associated mortality. No patients developed = grade 2 systemic hemorrhages. One patient developed a deep venous thrombosis while taking Tinzaparin, and three patients developed thromboembolic complications while off Tinzaparin secondary to thrombocytopenia. One patient was taken off study for increased liver function tests, possibly secondary to Tinzaparin. Conclusions: Thus far, daily prophylactic Tinzaparin has proven safe and effective in decreasing the incidence of thromboembolic disease in brain tumor patients. We plan a phase III study upon the safe completion of the last 7 patients on this phase II study. No significant financial relationships to disclose.
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Tinzaparin prophylaxis against thromboembolic complications in brain tumor patients
Journal of Clinical Oncology, 2006Co-Authors: J. J. Vredenburgh, D. A. Reardon, A. Desjardins, J. A. Quinn, J. N. Rich, Cindy Bohlin, Sith Sathornsumetee, Lawrence B. Marks, A. H. Friedman, H. S. FriedmanAbstract:1539 Background: Thromboembolic complications are common in brain tumor patients, contribute to the morbidity and mortality and complicate treatment. Twenty to 40% of brain tumor patients develop a deep venous thrombosis and/or pulmonary embolus during their course. Thromboembolic complications are the second leading cause of death in brain tumor patients. One of the low molecular weight heparins, Tinzaparin, has increased factor Xa activity as opposed to thrombin inhibition, which may improve the therapeutic:toxicity ratio. Methods: We report a phase II trial of prophylactic Tinzaparin for newly diagnosed brain tumor patients. Twenty-seven of the planned 40 patients have been accrued. Patients received daily Tinzaparin at a fixed dose of 4500 IU subcutaneously beginning a minimum of 48 hours post-operatively and a maximum of 4 weeks post-operatively. Patients were scheduled to receive Tinzaparin for 12 months. During chemotherapy cycles, the blood counts were monitored weekly. If the platelet count was <50,000, the Tinzaparin was held until the platelets were >100,000. Results: One of the patients developed a grade 3 CNS hemorrhage, necessitating cessation of the Tinzaparin, there have been no grade 4 or 5 CNS hemorrhages or treatment associated mortality. Also, there have been no ≥ grade 2 systemic hemorrhages. One patient developed a deep venous thrombosis while taking Tinzaparin, and three patients developed thromboembolic complications while off Tinzaparin secondary to thrombocytopenia. One patient was taken off study for increased liver function tests, possibly secondary to Tinzaparin. The patients have taken the Tinzaparin for 4–52 weeks, with a median of 18 weeks. Conclusions: Tinzaparin at a fixed prophylactic dose is safe and may decrease the incidence of thromboembolic complications in brain tumor patients. If the completed phase II study yields similar results, a phase III trial is warranted. No significant financial relationships to disclose.
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Tinzaparin prophylaxis against thromboembolic complications in brain tumor patients
Journal of Clinical Oncology, 2006Co-Authors: J. J. Vredenburgh, D. A. Reardon, A. Desjardins, J. A. Quinn, J. N. Rich, Cindy Bohlin, Sith Sathornsumetee, Lawrence B. Marks, A. H. Friedman, H. S. FriedmanAbstract:1539 Background: Thromboembolic complications are common in brain tumor patients, contribute to the morbidity and mortality and complicate treatment. Twenty to 40% of brain tumor patients develop a deep venous thrombosis and/or pulmonary embolus during their course. Thromboembolic complications are the second leading cause of death in brain tumor patients. One of the low molecular weight heparins, Tinzaparin, has increased factor Xa activity as opposed to thrombin inhibition, which may improve the therapeutic:toxicity ratio. Methods: We report a phase II trial of prophylactic Tinzaparin for newly diagnosed brain tumor patients. Twenty-seven of the planned 40 patients have been accrued. Patients received daily Tinzaparin at a fixed dose of 4500 IU subcutaneously beginning a minimum of 48 hours post-operatively and a maximum of 4 weeks post-operatively. Patients were scheduled to receive Tinzaparin for 12 months. During chemotherapy cycles, the blood counts were monitored weekly. If the platelet count was <...
Gerd Bendas - One of the best experts on this subject based on the ideXlab platform.
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the impact of the low molecular weight heparin Tinzaparin on the sensitization of cisplatin resistant ovarian cancers preclinical in vivo evaluation in xenograft tumor models
Molecules, 2017Co-Authors: Thomas Mueller, Daniel Bastian Pfankuchen, Martin Schlesinger, Kathleen Wantoch Von Rekowski, Franziska Reipsch, Gerd BendasAbstract:Resistance formation of tumors against chemotherapeutics is the major obstacle in clinical cancer therapy. Although low molecular weight heparin (LMWH) is an important component in oncology referring to guideline-based antithrombotic prophylaxis of tumor patients, a potential interference of LMWH with chemoresistance is unknown. We have recently shown that LMWH reverses the cisplatin resistance of A2780cis human ovarian cancer cells in vitro. Here we address the question whether this LMWH effect is also valid under in vivo conditions. Therefore, we established tumor xenografts of A2780 and cisplatin resistant A2780cis cells in nude mice and investigated the impact of daily Tinzaparin applications (10 mg/kg BW) on anti-tumor activity of cisplatin (6 mg/kg BW, weekly) considering the tumor growth kinetics. Intratumoral platinum accumulation was detected by GF-AAS. Xenografts of A2780 and A2780cis cells strongly differed in cisplatin sensitivity. As an overall consideration, Tinzaparin co-treatment affected the response to cisplatin of A2780cis, but not A2780 tumors in the later experimental time range. A subgroup analysis confirmed that initially smaller A2780cis tumors benefit from Tinzaparin, but also small A2780 xenografts. Tinzaparin did not affect cisplatin accumulation in A2780cis xenografts, but strongly increased the platinum content in A2780, obviously related to morphological differences in both xenografts. Although we cannot directly confirm a return of A2780cis cisplatin resistance by Tinzaparin, as shown in vitro, the present findings give reason to discuss heparin effects on cytostatic drug efficiency for small tumors and warrants further investigation.
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The Impact of the Low Molecular Weight Heparin Tinzaparin on the Sensitization of Cisplatin-Resistant Ovarian Cancers—Preclinical In Vivo Evaluation in Xenograft Tumor Models
Molecules (Basel Switzerland), 2017Co-Authors: Thomas Mueller, Daniel Bastian Pfankuchen, Martin Schlesinger, Kathleen Wantoch Von Rekowski, Franziska Reipsch, Gerd BendasAbstract:Resistance formation of tumors against chemotherapeutics is the major obstacle in clinical cancer therapy. Although low molecular weight heparin (LMWH) is an important component in oncology referring to guideline-based antithrombotic prophylaxis of tumor patients, a potential interference of LMWH with chemoresistance is unknown. We have recently shown that LMWH reverses the cisplatin resistance of A2780cis human ovarian cancer cells in vitro. Here we address the question whether this LMWH effect is also valid under in vivo conditions. Therefore, we established tumor xenografts of A2780 and cisplatin resistant A2780cis cells in nude mice and investigated the impact of daily Tinzaparin applications (10 mg/kg BW) on anti-tumor activity of cisplatin (6 mg/kg BW, weekly) considering the tumor growth kinetics. Intratumoral platinum accumulation was detected by GF-AAS. Xenografts of A2780 and A2780cis cells strongly differed in cisplatin sensitivity. As an overall consideration, Tinzaparin co-treatment affected the response to cisplatin of A2780cis, but not A2780 tumors in the later experimental time range. A subgroup analysis confirmed that initially smaller A2780cis tumors benefit from Tinzaparin, but also small A2780 xenografts. Tinzaparin did not affect cisplatin accumulation in A2780cis xenografts, but strongly increased the platinum content in A2780, obviously related to morphological differences in both xenografts. Although we cannot directly confirm a return of A2780cis cisplatin resistance by Tinzaparin, as shown in vitro, the present findings give reason to discuss heparin effects on cytostatic drug efficiency for small tumors and warrants further investigation.
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Low molecular weight heparin Tinzaparin antagonizes cisplatin resistance of ovarian cancer cells.
Biochemical pharmacology, 2015Co-Authors: Daniel Bastian Pfankuchen, Daniel Philipp Stölting, Martin Schlesinger, Hans-dieter Royer, Gerd BendasAbstract:Low molecular weight heparin (LMWH) is routinely used for antithrombotic treatment of cancer patients. Preclinical- and clinical data suggest that LMWH has beneficial effects for cancer patients beyond the prevention of thrombosis, i.e. by inhibiting metastasis. It is, however, unclear whether heparin has an impact on the efficiency of chemotherapy in cancer patients. Here we show that a therapeutic dosage of LMWH Tinzaparin reverses cisplatin resistance of A2780cis human ovarian cancer cells to the level of sensitive cells. This novel activity of Tinzaparin is associated with intense transcriptional reprogramming. Our gene expression profiling experiments revealed that 3776 genes responded to Tinzaparin treatment. For this reason Tinzaparin has a complex impact on diverse biological processes. We discovered that Tinzaparin inhibits the expression of genes that mediate cisplatin resistance of A2780cis cells. In contrast Tinzaparin induced the expression of genes that antagonize drug resistance. This activity of Tinzaparin is mediated by cell surface proteoglycans, since enzymatic cleavage of heparan sulfates prevented the reversal of cisplatin resistance. These data indicate that cell surface heparan sulfate proteoglycans play an important role for chemotherapy resistance. The results of this study shed a new light on LMWH application in cancer therapy and suggest Tinzaparin as promising treatment option of ovarian cancer patients in combination with anticancer drugs. Future clinical trials are needed to validate these findings.
Shaker A. Mousa - One of the best experts on this subject based on the ideXlab platform.
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elevation of plasma von willebrand factor and tumor necrosis factor a in obese subjects and their reduction by the low molecular weight heparin Tinzaparin
International Angiology, 2005Co-Authors: Shaker A. MousaAbstract:AIM Increased plasma-soluble von Willebrand factor (vWF) level, a marker of vascular endothelial cell dysfunction, is a predictor of atherosclerotic cardiovascular disease. We compared associations between vWF level and markers of inflammation as well as the effects of LMWH in obese as compared to healthy human subjects. METHODS Plasma samples were obtained from healthy volunteers (n=32) and obese subjects (n=12) before and after administration of a single subcutaneous dose of Tinzaparin, given at 75 IU/kg once a day, a deep vein thrombosis prophylaxis dose. Plasma samples were analyzed for vWF and tumor necrosis factor-alfa (TNF-alfa) using specific and sensitive ELISA. RESULTS Obese subjects showed relatively higher plasma levels of TNF-alfa compared with normal-weight subjects. Regression analysis showed that plasma vWF levels to be directly associated with the presence of higher plasma levels of TNF-alfa in these obese subjects. Tinzaparin significantly reduced elevated plasma levels of both vWF and TNF-a levels (P<0.01). CONCLUSIONS Plasma values of vWF and TNF-alfa are higher in obese than in normal-weight individuals. Treatment with Tinzaparin lowers plasma levels of TNF-alfa in both obese and normal-weight subjects. The levels of vWF were higher in obese subjects than in normal-weight ones, which might be due to the higher levels of circulating TNF-alfa. Tinzaparin reduced vWF levels in these obese subjects.
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Elevation of plasma von Willebrand factor and tumor necrosis factor-a in obese subjects and their reduction by the low molecular weight heparin Tinzaparin.
International angiology : a journal of the International Union of Angiology, 2005Co-Authors: Shaker A. MousaAbstract:Increased plasma-soluble von Willebrand factor (vWF) level, a marker of vascular endothelial cell dysfunction, is a predictor of atherosclerotic cardiovascular disease. We compared associations between vWF level and markers of inflammation as well as the effects of LMWH in obese as compared to healthy human subjects. Plasma samples were obtained from healthy volunteers (n=32) and obese subjects (n=12) before and after administration of a single subcutaneous dose of Tinzaparin, given at 75 IU/kg once a day, a deep vein thrombosis prophylaxis dose. Plasma samples were analyzed for vWF and tumor necrosis factor-alfa (TNF-alfa) using specific and sensitive ELISA. Obese subjects showed relatively higher plasma levels of TNF-alfa compared with normal-weight subjects. Regression analysis showed that plasma vWF levels to be directly associated with the presence of higher plasma levels of TNF-alfa in these obese subjects. Tinzaparin significantly reduced elevated plasma levels of both vWF and TNF-a levels (P<0.01). Plasma values of vWF and TNF-alfa are higher in obese than in normal-weight individuals. Treatment with Tinzaparin lowers plasma levels of TNF-alfa in both obese and normal-weight subjects. The levels of vWF were higher in obese subjects than in normal-weight ones, which might be due to the higher levels of circulating TNF-alfa. Tinzaparin reduced vWF levels in these obese subjects.
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Anti-angiogenic mechanisms and efficacy of the low molecular weight heparin, Tinzaparin: anti-cancer efficacy.
Oncology reports, 2004Co-Authors: Shaker A. Mousa, Seema MohamedAbstract:Inhibitors of angiogenesis are potential anti-cancer agents in that they deprive tumors of the blood necessary for growth and metastasis. The anti-angiogenic efficacy of Tinzaparin, a known anticoagulant low molecular weight heparin (LMWH), was examined in vitro in endothelial cell tube formation assay and in vivo in the chick chorioallantoic membrane model. The observed anti-angiogenic effects of Tinzaparin were shown to be dose-related and dependent on the relatively higher molecular weight Tinzaparin fragments. These experiments demonstrated that Tinzaparin is a potent inhibitor of angiogenesis (ED90-100 range, 0.05-0.1 mg) regardless of the angiogenic factor and suggest that its effect is mediated via cellular release of tissue factor pathway inhibitor (TFPI). This was evident by the reversal of either Tinzaparin or r-TFPI anti-angiogenesis efficacy by a specific monoclonal TFPI antibody. The ED90-100 for the inhibition of angiogenesis for r-TFPI ranged from 0.01 to 0.03 mg in the chorioallantoic membrane model regardless of the proangiogenic factor. In addition, either Tinzaparin or r-TFPI inhibited the growth of colon carcinoma tumors, human fibrosarcoma tumors, and human lung carcinoma in the chorioallantoic membrane tumor implant model. Thus, the LMWH Tinzaparin, in addition to its anticoagulant effects, may offer important benefits in treatment of cancer and other disorders supported by pathologic angiogenesis.
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Antimetastatic effect of Tinzaparin, a low-molecular-weight heparin.
Journal of thrombosis and haemostasis : JTH, 2003Co-Authors: Ali Amirkhosravi, Shaker A. Mousa, Mildred Amaya, John L. FrancisAbstract:The importance of coagulation activation in cancer patients is suggested by the clinical finding of hypercoagulability, experimental enhancement of metastasis and angiogenesis by coagulation factors such as tissue factor (TF) and thrombin and the possible antitumor effects of anticoagulant agents. Tinzaparin is a low-molecular-weight heparin (LMWH) with a relatively high molecular weight distribution and high sulfate to carboxylate ratio. In addition to its ability to inhibit thrombin and factor Xa, Tinzaparin is particularly effective at releasing endothelial tissue factor pathway inhibitor (TFPI), the natural inhibitor of both procoagulant and non-coagulant effects of TF. The present study was undertaken to investigate the effect of Tinzaparin on lung metastasis using a B16 melanoma model in experimental mice. Tinzaparin's anticoagulant effect in mice and its ability to release TFPI from human endothelial cells at various time points were demonstrated. Subcutaneous (s.c.) injection of Tinzaparin (10 mg kg-1) 4 h before intravenous administration of melanoma cells (2.0 x 105) markedly (89%) reduced lung tumor formation (3 +/- 2) compared with controls (31 +/- 23; P < 0.001). In a second group of animals, Tinzaparin (10 mg kg-1, s.c.) administered daily for 14 days following the initial (pretumor cell) dose, before assessment of lung seeding, reduced tumor formation by 96% (P < 0.001). No bleeding problems were observed in any of the Tinzaparin-treated animals, despite a 4-fold prolongation of the whole blood clotting time after a single s.c. dose of Tinzaparin (10 mg kg-1). Administration of tumor cells (2 x 106) caused a rapid and significant fall in platelet count 15 min after injection (a sensitive marker of intravascular coagulation) in controls (939 +/- 37 vs. 498 +/- 94 x 106 mL-1, P < 0.01), but this was prevented by Tinzaparin treatment (921 +/- 104 x 106 mL-1). These data provide further experimental evidence to support the potential for LMWH as antimetastatic agents.
C Dubois - One of the best experts on this subject based on the ideXlab platform.
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PO-34 - Optimal doses of Tinzaparin to reduce both cancer-associated thrombosis and tumor growth in a mouse model of ectopic pancreatic syngeneic tumor.
Thrombosis research, 2016Co-Authors: L Panicot-dubois, S Mezouar, L Plantureux, L Crescence, C Frère, C DuboisAbstract:In clinical studies, thromboprophylaxis with low-molecular-weight heparins (LMWHs) has been demonstrated to reduce the risk of venous thromboembolism and to improve outcomes in cancer patients. Moreover, preclinical models have previously suggested that LMWHs may also offer additional benefits through direct antitumor properties. However, the optimal doses of LMWHs that may prevent both cancer-related thrombosis and tumor development are yet unknown. The goal of this study was to determine the optimal doses of Tinzaparin that may prevent both cancer-related thrombosis and tumor development in a syngeneic ectopic model of pancreatic cancer. The optimal doses of Tinzaparin to generate a plasma anti-Xa activity >0.2IU/mL were determined in vivo following injection into wild type mice.The syngeneic ectopic model of cancer was induced in wild-type mice using the mouse pancreatic cancer cell line Panc02. Mice were injected daily with 200, 300IU/kg or 400IU/kg, or placebo from day 8 to 25 following tumor induction. Kinetics of thrombus formation and fibrin generation were determined in real time by digital real time intravital microscopy in mice bearing a tumor treated with Tinzaparin or placebo. The growth of the tumor and the bleeding times were measured and compared in the different groups of mice. Plasma anti-Xa levels <0.2IU/mL were observed with Tinzaparin doses ranging from 0 to 150IU/kg, whereas plasma anti-Xa activities >0.2IU/mL were obtained with >200IU/kg Tinzaparin doses. At day 25 following tumor induction, the kinetics of thrombosis were not affected in mice treated with daily 200IU/kg Tinzaparin compared to controls whereas it was strongly affected in mice treated with daily 300 and 400IU/kg Tinzaparin. Interestingly, a significant decrease in tumor growth was observed in mice treated with 200, 300 and 400IU/kg Tinzaparin in comparison to controls, with no significant difference between these groups. Bleeding times were similar to control mice in mice treated with 200IU/kg Tinzaparin, but significantly increased in mice treated with 300IU/kg and 400IU/kg Tinzaparin. At the dose of 200IU/kg, Tinzaparin treatment significantly inhibits tumor growth but did not affect the thrombotic phenotype in mice developing a cancer. When 300 and 400IU/kg dose are used, Tinzaparin treatment decreases both cancer-related thrombotic phenotype and tumor growth, but at the price of a significant increase in the bleeding time. © 2016 Elsevier Ltd. All rights reserved.
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PO-34 - Optimal doses of Tinzaparin to reduce both cancer-associated thrombosis and tumor growth in a mouse model of ectopic pancreatic syngeneic tumor.
Thrombosis Research, 2016Co-Authors: L Panicot-dubois, S Mezouar, L Plantureux, L Crescence, C Frère, C DuboisAbstract:Introduction In clinical studies, thromboprophylaxis with low-molecular-weight heparins (LMWHs) has been demonstrated to reduce the risk of venous thromboembolism and to improve outcomes in cancer patients. Moreover, preclinical models have previously suggested that LMWHs may also offer additional benefits through direct antitumor properties. However, the optimal doses of LMWHs that may prevent both cancer-related thrombosis and tumor development are yet unknown. Aim The goal of this study was to determine the optimal doses of Tinzaparin that may prevent both cancer-related thrombosis and tumor development in a syngeneic ectopic model of pancreatic cancer. Materials and Methods The optimal doses of Tinzaparin to generate a plasma anti-Xa activity > 0.2 IU/mL were determined in vivo following injection into wild type mice.The syngeneic ectopic model of cancer was induced in wild-type mice using the mouse pancreatic cancer cell line Panc02. Mice were injected daily with 200, 300 IU/kg or 400 IU/kg, or placebo from day 8 to 25 following tumor induction. Kinetics of thrombus formation and fibrin generation were determined in real time by digital real time intravital microscopy in mice bearing a tumor treated with Tinzaparin or placebo. The growth of the tumor and the bleeding times were measured and compared in the different groups of mice. Results Plasma anti-Xa levels 0.2 IU/mL were obtained with > 200 IU/kg Tinzaparin doses. At day 25 following tumor induction, the kinetics of thrombosis were not affected in mice treated with daily 200 IU/kg Tinzaparin compared to controls whereas it was strongly affected in mice treated with daily 300 and 400 IU/kg Tinzaparin. Interestingly, a significant decrease in tumor growth was observed in mice treated with 200, 300 and 400 IU/kg Tinzaparin in comparison to controls, with no significant difference between these groups. Bleeding times were similar to control mice in mice treated with 200 IU/kg Tinzaparin, but significantly increased in mice treated with 300 IU/kg and 400 IU/kg Tinzaparin. Conclusions At the dose of 200 IU/kg, Tinzaparin treatment significantly inhibits tumor growth but did not affect the thrombotic phenotype in mice developing a cancer. When 300 and 400 IU/kg dose are used, Tinzaparin treatment decreases both cancer-related thrombotic phenotype and tumor growth, but at the price of a significant increase in the bleeding time.
