A randomized clinical trial of combination chemotherapy with and without low‐molecular‐weight heparin in small cell lung cancer

Altınbaş, Mustafa; Çoşkun, H.Ş.; Er, Özlem; Özkan, Metin; Eser, Bülent; Ünal, Ali Ekrem; Çetin, Mustafa; Soyuer, Serdar

doi:10.1111/j.1538-7836.2004.00871.x

Cited by 432 publications

(310 citation statements)

References 17 publications

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“…Low molecular weight heparin (LMWH) may attenuate these events through multiple mechanisms, including 1) by directly inhibiting thrombin or other coagulation proteins by catalyzing antithrombin, 3 2) by indirectly inhibiting thrombin formation by stimulating the release of tissue factor pathway inhibitor, an effective inhibitor of TF-mediated coagulation, 3 and 3) by inhibiting VEGF-A. 3 growth in several cancers in early, 32,33 but not advanced disease. 21 We show that LMWH significantly reduced tumor cell proliferation and thrombin generation in vitro and in vivo.…”

Section: Discussionmentioning

confidence: 99%

Thrombin induces osteosarcoma growth, a function inhibited by low molecular weight heparin in vitro and in vivo

Ichikawa

Cole

Magnussen

et al. 2011

Cancer

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BACKGROUND: Procoagulant states, leading to activation of the coagulation protease thrombin, are common in cancer and portend a poor clinical outcome. Although procoagulant states in osteosarcoma patients have been described, studies exploring osteosarcoma cells' ability to directly contribute to procoagulant activity have not been reported. This study explores the hypothesis that osteosarcoma can regulate thrombin generation and proliferate in response to thrombin, and that attenuating thrombin generation with anticoagulants can slow tumor growth. METHODS: Pathologic analysis of osteosarcoma with adjacent venous thrombus was performed. In vitro proliferation assays, cell-based coagulant activity assays, and quantification of coagulation cofactor expression were performed on human and murine osteosarcoma cell lines with varying aggressiveness. The efficacy of low molecular weight heparin (LMWH) attenuation of tumor-dependent thrombin generation and growth in vitro and in vivo was determined. RESULTS: Venous thrombi adjacent to osteosarcoma were found to harbor tumor surrounded by fibrin expressing coagulation cofactors, a finding associated with poor clinical outcome. More aggressive osteosarcoma cell lines had greater surface expression of procoagulant factors and generated more thrombin than less aggressive cell lines and were found to proliferate in response to thrombin. Treatment with LMWH reduced in vitro osteosarcoma proliferation and procoagulant activity as well as tumor growth in vivo. CONCLUSIONS: These findings suggest that elements of the coagulation cascade may play a role in and represent a pharmaceutical target to disrupt osteosarcoma growth. They also have broader implications, as they suggest that, to be effective, dosing of anticoagulants must take into account an individual tumor's capacity to generate thrombin. Cancer 2012;118:2494

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Section: Discussionmentioning

confidence: 99%

Thrombin induces osteosarcoma growth, a function inhibited by low molecular weight heparin in vitro and in vivo

Ichikawa

Cole

Magnussen

et al. 2011

Cancer

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“…This finding strongly indicates that inhibition of P-selectin is one of the main cancer inhibitory activities of heparin [91]. Based on the encouraging observations with heparin treatment evaluated in retrospective studies, several recent prospective clinical trials have been performed to study this phenomenon [92][93][94][95]. The promising results from the clinical studies, primarily in earlier stage patients together with the experimental evidence suggests that heparin treatment directly affect the metastasis rather than by simple inhibition of coagulation [35].…”

Section: Platelets As Therapeutic Targets For Anti-cancer Therapiesmentioning

confidence: 99%

The role of platelet activation in tumor metastasis

Borsig¹

2008

Expert Review of Anticancer Therapy

180

143

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“…The effect of heparin on tumors includes interference with cancer-induced hypercoagulation, cancer cell proliferation, degradation of the extra-cellular matrix (involving the heparan sulfate chains of cell surface and extracellular matrix proteoglycans), angiogenesis, selectin-mediated binding of platelets and cancer cells, growth factors and their receptors, hepara- nase, tumor progression, and metastasis [13,14] . Heparin was proposed to have a role in maintaining the effects of chemotherapeutic drugs, as both UFH and LMWH have been shown to act as chemotherapy sensitizers [4,5] . In our evaluation of the influence of heparin on tumor cell proliferation, cell cycle and apoptosis, we found that it could inhibit proliferation of PC-3M tumor cells and arrest them in the G 0 /G 1 phase.…”

Section: Effect Of Heparin On Brdu Incorporation and Ki67 Expression mentioning

confidence: 99%

“…Two trials (FAMOUS and MALT) previously studied the effect of unfractionated heparin (UFH) [4] or low molecular weight heparin (LMWH) [5] in patients with small cell lung cancer. In both of these studies, a statistically significant survival advantage was observed in patients randomized to chemotherapy plus UFH or LMWH relative to patients who received chemotherapy alone.…”

Section: Acta Pharmacologica Sinica Npgmentioning

confidence: 99%

Roles of vimentin and 14-3-3 zeta/delta in the inhibitory effects of heparin on PC-3M cell proliferation and B16-F10-luc-G5 cells metastasis

et al. 2012

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Aim: To investigate the inhibitory effects of heparin on PC-3M cells proliferation in vitro and B16-F10-luc-G5 cells metastasis in Balb/c nude mice and identify the protein expression patterns to elucidate the action mechanism of heparin. Methods: Human prostate cancer PC-3M cells were incubated with heparin 0.5 to 125 μg/mL for 24 h. The proliferation of PC-3M cells was assessed by MTS assay. BrdU incoporation and Ki67 expression were detected using a high content screening (HCS) assay. The cell cycle and apoptosis of PC-3M cells were tested by flow cytometry. B16-F10-luc-G5 cardinoma cells were injected into the lateral tail vein of 6-week old male Balb/c nude mice and heparin 30 mg/kg was administered iv 30 min before and 24 h after injection. The metasis of B16-F10-luc-G5 cells was detected by bioluminescence assay. Activated partial thromboplastin time (APTT) and hemorheological parameters were measured on d 14 after injection of B16-F10-luc-G5 carcinoma cells in Balb/c mice. The global protein changes in PC-3M cells and frozen lung tissues from mice burdened with B16-F10-luc-G5 cells were determined by 2-dimensional gel electrophoresis and image analysis. The protein expression of vimentin and 14-3-3 zeta/delta was measured by Western blot. The mRNA transcription of vimentin, transforming growth factor (TGF)-β, E-cadherin, and α v -integrin was measured by RT-PCR. Results: Heparin 25 and 125 μg/mL significantly inhibited the proliferation, arrested the cells in G 1 phase, and suppressed BrdU incorporation and Ki67 expression in PC-3M cells compared with the model group. But it had no significant effect on apoptosis of PC-3M cells. Heparin 30 mg/kg markedly inhibits the metastasis of B16-F10-luc-G5 cells on day 8. Additionally, heparin administration maintained relatively normal red blood hematocrit but had no influence on APTT in nude mice burdened with B16-F10-luc-G5 cells. Thirty of down-regulated protein spots were identified after heparin treatment, many of which are related to tumor development, extracellular signaling, energy metabolism, and cellular proliferation. Vimentin and 14-3-3 zeta/delta were identified in common in PC-3M cells and the lungs of mice bearing B16-F10-luc-G5 carcinoma cells. Heparin 25 and 125 μg/mL decreased the protein expression of vimentin and 14-3-3 zeta/delta and the mRNA expression of α v -integrin. Heparin 125 μg/mL decreased vimentin and E-cadherin mRNA transcription while increased TGF-β mRNA transcription in the PC-3M cells, but the differences were not significant. Transfection of vimentin-targeted siRNA for 48 h significantly decreased the BrdU incoporation and Ki67 expression in PC-3M cells. Conclusion: Heparin inhibited PC-3M cell proliferation in vitro and B16-F10-luc-G5 cells metastasis in nude mice by inhibition of vimentin, 14-3-3 zeta/delta, and α v -integrin expression.

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A randomized clinical trial of combination chemotherapy with and without low‐molecular‐weight heparin in small cell lung cancer

Cited by 432 publications

References 17 publications

Thrombin induces osteosarcoma growth, a function inhibited by low molecular weight heparin in vitro and in vivo

Thrombin induces osteosarcoma growth, a function inhibited by low molecular weight heparin in vitro and in vivo

The role of platelet activation in tumor metastasis

Roles of vimentin and 14-3-3 zeta/delta in the inhibitory effects of heparin on PC-3M cell proliferation and B16-F10-luc-G5 cells metastasis

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