Low Molecular Weight Heparin, Therapy With Dalteparin, and Survival in Advanced Cancer: The Fragmin Advanced Malignancy Outcome Study (FAMOUS)

Kakkar, Ajay K.; Levine, Mark; Kadziola, Zbigniew; Lemoine, Nicholas R.; Low, Vanessa; Patel, Heman K.; Rustin, G. J. S.; Thomas, Michael J.; Quigley, Mary; Williamson, R. C. N.

doi:10.1200/jco.2004.10.002

Cited by 630 publications

(442 citation statements)

References 26 publications

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“…These data extend previous observations that have implicated antimetastatic effects for heparin and HLGAGs in animal model systems (21)(22)(23)(24)(25)(26). Clinical studies have also indicated that heparin and HLGAGs may prolong survival of patients with cancer with solid tumors (3)(4)(5).…”

Section: Discussionsupporting

confidence: 76%

“…Highly sulfated heparan sulfate glycosaminoglycans, such as heparin, are commonly used to prevent venous thromboembolism, which is a common complication in patients with cancer as well. Heparin and heparin-like glycosaminoglycans (HLGAGs) have also been shown to prolong survival of patients with cancer, suggesting an antimetastatic effect for these compounds (3)(4)(5). The applicability of heparin in cancer therapy is limited because of its strong anticoagulant activity, but HLGAGs with less undesired effects on blood coagulation have been developed.…”

Section: Introductionmentioning

confidence: 99%

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Heparin-like Polysaccharides Reduce Osteolytic Bone Destruction and Tumor Growth in a Mouse Model of Breast Cancer Bone Metastasis

Pollari

Käkönen

Mohammad

et al. 2012

Molecular Cancer Research

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TGF-b regulates several steps in cancer metastasis, including the establishment of bone metastatic lesions. TGF-b is released from bone during osteoclastic bone resorption and it stimulates breast cancer cells to produce osteolytic factors such as interleukin 11 (IL-11). We conducted a cell-based siRNA screen and identified heparan sulfate 6-Osulfotransferase 2 (HS6ST2) as a critical gene for TGF-b-induced IL-11 production in highly bone metastatic MDA-MB-231(SA) breast cancer cells. HS6ST2 attaches sulfate groups to glucosamine residues in heparan sulfate glycosaminoglycans. We subsequently showed how heparin and a high-molecular-weight Escherichia coli K5-derived heparin-like polysaccharide (K5-NSOS) inhibited TGF-b-induced IL-11 production in MDA-MB-231 (SA) cells. In addition, K5-NSOS inhibited bone resorption activity of human osteoclasts in vitro. We evaluated the therapeutic potential of K5-NSOS and fragmin in a mouse model of breast cancer bone metastasis. MDA-MB-231 (SA) cells were inoculated into the left cardiac ventricle of athymic nude mice which were treated with fragmin, K5-NSOS, or vehicle once a day for four weeks. Both heparin-like glycosaminoglycans inhibited weight reduction, decreased osteolytic lesion area, and reduced tumor burden in bone. In conclusion, our data imply novel mechanisms involved in TGF-b induction and support the critical role of heparan sulfate glycosaminoglycans in cancer metastasis as well as indicate that K5-NSOS is a potential antimetastatic and antiresorptive agent for cancer therapy. This study illustrates the potential to translate in vitro siRNA screening results toward in vivo therapeutic concepts. Mol Cancer Res; 10(5); 597-604. Ó2012 AACR.

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Section: Discussionsupporting

confidence: 76%

Section: Introductionmentioning

confidence: 99%

Heparin-like Polysaccharides Reduce Osteolytic Bone Destruction and Tumor Growth in a Mouse Model of Breast Cancer Bone Metastasis

Pollari

Käkönen

Mohammad

et al. 2012

Molecular Cancer Research

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“…Over the past 20 years, there has been increasing clinical evidence that anticoagulants have antitumour effects reducing the risk of cancer in patients with VTE and improving survival in patients with advanced malignancy (Zacharski et al, 1981;Schulman and Lindmarker, 2000;Kakkar et al, 2004). Cancer patients with VTE are at increased risk of second malignancies, but further work is needed before specific guidelines for their management would be appropriate.…”

Section: Discussionmentioning

confidence: 99%

The risk of a second cancer after hospitalisation for venous thromboembolism

et al. 2005

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Although venous thromboembolism (VTE) is common in patients with cancer, it is not known if it is associated with risk of a second malignancy. Using the Danish Cancer Registry and National Registry of Patients, we studied a population-based cohort of 6285 patients with cancer who had an episode of VTE. The risk of a second cancer was compared with that among 30 713 cancer patients without VTE, matched for age, sex, cancer site and year of diagnosis. Overall, the relative risk for a second cancer diagnosis was 1.3 (95% confidence interval (CI) 1.1 -1.4). However, the excess risk varied with the time from the initial cancer diagnosis to the thrombotic event. If the thrombotic episode occurred within the first year, the relative risk for a second cancer was 1.0 (95% CI 0.9 -1.3), but if the VTE occurred more than 1 year after the initial cancer, the overall relative risk for a second cancer was 1.4 (95% CI 1.2 -1.7), with strong associations for cancers of the digestive organs, ovary and prostate. The association between VTE and subsequent incident cancer extends to patients who already have had a cancer diagnosis.

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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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Low Molecular Weight Heparin, Therapy With Dalteparin, and Survival in Advanced Cancer: The Fragmin Advanced Malignancy Outcome Study (FAMOUS)

Abstract: Dalteparin administration did not significantly improve 1-year survival rates in patients with advanced malignancy. However, the observed improved survival in a subgroup of patients with a better prognosis suggests a potential modifying effect of dalteparin on tumor biology.

Cited by 630 publications

References 26 publications

Heparin-like Polysaccharides Reduce Osteolytic Bone Destruction and Tumor Growth in a Mouse Model of Breast Cancer Bone Metastasis

Heparin-like Polysaccharides Reduce Osteolytic Bone Destruction and Tumor Growth in a Mouse Model of Breast Cancer Bone Metastasis

The risk of a second cancer after hospitalisation for venous thromboembolism

The role of platelet activation in tumor metastasis

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