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Editorial article
Antineoplastic effects of heparins
Efectos anticancerígenos de las heparinas
Amparo Santamaríaa,
Corresponding author
masantamaria@vinaloposalud.com

Corresponding author.
, Milagros Suitob
a Servicio de Hematología, Hospital Universitario del Vinalopó y Torrevieja, Alicante, Spain
b Unidad de Hemostasia y Trombosis, Hospital Universitario Vall d’Hebron, Barcelona, Spain
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    "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">65 years ago&#44; it was questioned whether heparin had non-antithrombotic effects&#44; such as an effect on the placenta or anticancer effects&#44; and if this possible effect could be used in cancer patients to improve their overall survival&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#8211;7</span></a> But the truth is that although various studies have been carried out in the last 20 years&#44;<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6&#8211;16</span></a> we do not know exactly how they work&#44; and the clinical results are currently inconclusive in terms of their use as an adjunct treatment in cancer patients&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">Therefore&#44; in recent years&#44; research has focused on the use of new technologies to use the part of the low molecular weight heparin &#40;LMWH&#41; in a more targeted and personalised way&#44; such as the development of nanoparticles through the structural modification of the LMWH&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">It has already been shown that patients with malignant neoplasms treated with LMWH&#44; together with cancer treatment&#44; survive longer&#44; not only because they avoid thromboembolic phenomena&#44; but also because of a possible anti-tumour effect independent of its anticoagulant effect&#44; probably antiangiogenic&#44; in addition to others already described&#46; These results have been corroborated in subsequent meta-analyses&#44; where not only the effect on mortality favoured the LMWHs &#40;<span class="elsevierStyleItalic">odds ratio</span> &#91;OR&#93;&#58; 0&#46;71&#41;&#44; but in addition&#44; the risk of serious bleeding complications was lower with LMWHs &#40;OR&#58; 0&#46;57&#41;&#44; although this did not reach statistical significance compared to unfractionated heparin&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> This meta-analysis also concludes that LMWHs are equivalent in preventing the recurrence of thrombotic events&#46; In the multivariate analysis of the study&#44; heparin proved to be an independent prognostic factor&#46; In this case&#44; patients with thrombosis and those treated with heparin survived longer with any of the prescribed regimens&#44; in comparison to those who did not suffer from thrombosis&#44; which in itself is associated with a worse prognosis&#44; due to the comorbidity involved in a thrombotic phenomenon&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">But what has really aroused scientific curiosity is to understand the possible mechanisms of the anti-tumoral action of heparins&#46; In the last 20 years these mechanisms of action have been studied and there are &#8220;proofs of concept&#8221; that show that they do exist&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;18</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">It is believed that the anti-tumour effect of heparins is due largely to their belonging to the family of glycosaminoglycans &#40;GAGs&#41;&#44; which are distributed in the extracellular matrix and regulate cell growth&#44; which could be carried out by different mechanisms&#46; These mechanisms include the antiangiogenic effect either by blocking the heparanase enzymes&#44; blocking the tissular factor or inhibiting the thrombin&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">Thrombin inhibition would impair cell growth in both clotting-dependent and -non-dependent manners&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#8211;10</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">Fibrin would also play an important role&#44; since the coagulation system and fibrinolysis are involved in healing as a regulator of the angiogenesis and the situations of hypoxia&#44; inflammation and tissue damage release angiogenic factors&#46; In tumour tissues the coagulation&#47;fibrinolysis system is unbalanced&#44; with an increased fibrin production and inhibition of the fibrinolysis system&#46; This does not only give rise to thrombosis&#44; but it can also stimulate angiogenesis&#59; supporting the development of tumour cells&#46; The generation of thrombin would lead to depositing fibrin around tumour cells thereby preventing cell adhesion and angiogenesis&#46;<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">7&#8211;10</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">Other mechanisms of action include&#58; the inhibition of platelet adhesion and the inhibition of extracellular matrix formation &#40;by blocking the heparanase action&#44; which would prevent the extracellular matrix from degradation and the release of cytokines into the tumour microenvironment&#41;&#59; the inhibition of the metastatic phenomenon &#40;via the blockade of the action of the P-selectin and L-selectin adhesion molecules contributing to metastases&#41;&#59; and some <span class="elsevierStyleItalic">in vitro</span> studies even suggest that heparins play a role as chemosensitisers&#46;<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">7&#8211;10</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">It can be concluded that some LMWH have been shown to have antiangiogenic effects <span class="elsevierStyleItalic">in vitro</span> and <span class="elsevierStyleItalic">in vivo</span>&#46; In human leukaemia&#44; lung cancer&#44; and breast cancer cells&#44; bemiparin has been shown to inhibit the formation of new capillaries and endothelial migration&#44; induced by VEGF and fibroblast growth factor 2 &#40;FGF-2&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> In addition&#44; bemiparin&#44; but not unfractionated heparin &#40;UFH&#41;&#44; showed an antiangiogenic and antivasculogenic effect in cell cultures of the umbilical vein endothelial cells and the endothelial progenitor cells&#44; so it is important to choose the drug and its appropriate doses&#46; Other LMWHs such as enoxaparin and tinzaparin&#44; which are widely used in our environment&#44; have also demonstrated these effects&#44; such as heparanase inhibition or endothelial protection&#44; respectively&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#8211;8</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">But how many studies have been conducted so far and what is the evidence&#63; Since 1992 several studies have been carried out&#46; There have been at least 8 studies<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9&#8211;16</span></a> with different heparins&#44; such as unfractionated heparin or LMWH such as bemiparin&#44; tinzaparin&#44; dalteparin or enoxaparin&#46; Five described positive results in terms of overall survival&#44; but 3 did not find this improvement&#46; It must be said that these studies included resected non-small cell lung carcinomas&#44; and pancreatic carcinomas&#44; with or without thrombosis&#44; and in different stages&#44; hence the great variability of results&#46; The Lebeau et al&#46; studies<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> with calcium heparin in 1994&#44; the ABEL study<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> with bemiparin in 2013&#44; the FAMOUS study<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> with dalteparin in 2004&#44; all found differences in overall survival&#44; but no improvements were observed in the RASTEN study<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> with enoxaparin in 2017&#44; the NIVALT-8 study with nadroparin in 2016&#44;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> or the TILT study with tinzaparin in 2017&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> The results of the meta-analysis are contradictory because the included studies are heterogeneous with aggressive tumours in different stages&#44; and with different prognoses&#44; treatments&#44; etc&#46; Therefore&#44; the results have not been conclusive&#44; and in the majority of cases the recommendations are to study the biomarkers to practise a more personalised medicine&#44; and to conduct studies with more homogeneous populations&#46; What these results have shown is a low level of evidence&#44; and not a demonstration of improvement in survival with the use of LMWH as an adjunctive treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">However&#44; studies are currently being conducted on the tumour vascular normalisation hypothesis that has impacted in the field of new drug development and whose mechanism of action is antiangiogenic&#44; like the LMWHs&#46; The hypothesis posits that rather than destroying tumour vessels&#44; the antiangiogenic drugs restore tumour veins and normalize the structure and function of the tumour vasculature&#44; improving oxygenation and sensitivity to drug release&#46; Hence the research has focused on the anti-angiogenic mechanisms of heparin&#46; Some studies have shown that the dissolution of microthrombi and other proteins in the tumour microenvironment reduces interstitial pressure and this can improve the penetration of anti-tumour drugs&#46; Preclinical phase studies have shown that LMWH is a potent inhibitor of VEGF&#44; and it can temporarily normalise vasculature during antiangiogenic therapy&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">Nowadays&#44; nanopharmaceuticals have already been designed using this characteristic of LMWH with a potent normalisation of the vasculature&#44; achieving good results in the modulation of the tumour microenvironment and enabling the anti-tumour drug to reach the tumour tissue and even improving the sensitivity of the tumour cells in immunotherapy&#46; These findings are the theoretical basis for future combined anticancer therapies&#44; as well as synergistic effects with other immunotherapies&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">In conclusion&#44; <span class="elsevierStyleItalic">in vitro</span> evidence exists of the anti-cancer effect of LMWH&#44; but the studies carried out are heterogeneous and with contradictory results&#44; so no improvement in survival rates have been seen that support the use of LMWH as an adjunctive treatment&#46; But it seems that progress is being made in other directions&#44; looking for new formulations or forms of administration&#44; such as nanoparticles&#44; that would have anticancer effects and that open a future to heparin&#44; in the fight against cancer&#46;</p></span>"
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Article information
ISSN: 23870206
Original language: English
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es en pt

¿Es usted profesional sanitario apto para prescribir o dispensar medicamentos?

Are you a health professional able to prescribe or dispense drugs?

Você é um profissional de saúde habilitado a prescrever ou dispensar medicamentos