Anti-cancer properties of low-molecular-weight heparin: Preclinical evidence

2009 ◽  
Vol 102 (08) ◽  
pp. 258-267 ◽  
Author(s):  
Lars Petersen ◽  
Shaker Mousa
Keyword(s):  
Molecular Weight ◽  
Clinical Trials ◽  
Unfractionated Heparin ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Tumour Progression ◽  
Coagulation Cascade ◽  
Low Molecular Weight ◽  
Anti Cancer ◽  
The Impact

SummaryMalignant conditions are frequently associated with a hypercoaguable state, with recurrent thrombosis due to the impact of cancer cells and chemotherapy or radiotherapy on the coagulation cascade. Heparin and, its pharmacokinetically improved versions, low-molecular-weight heparins (LMWH) are effective in the prevention and treatment of thromboembolic events in cancer patients. There are several lines of preclinical evidence suggesting potential benefits of LMWH in hypercoagulation and thrombosis as well as in various processes involved in tumour growth and metastasis.Tinzaparin is a LMWH produced by controlled enzymatic depolymerisation of unfractionated heparin. The efficacy of tinzaparin has been documented in several clinical trials across various conditions and in special patient populations.The main objective of this review is to present the existing knowledge on the preclinical anti-cancer properties of tinzaparin and other LMWH.The evidence for tinzaparin, as well as other LMWH, regarding interference with cancer-induced hypercoagulation, cancer cell proliferation, degradation of extra-cellular matrix, angiogenesis, selectin-mediated binding of platelet and cancer cells, chemokine signalling, tumour progression, and metastasis are reviewed. Certain clinical trials suggest improved survival of cancer patients with deep venous thrombosis treated with LMWH versus unfractionated heparin and when added to the promising preclinical anti-cancer properties of LMWH this warrants further investigations in prospective, randomised, controlled clinical trials in cancer patients.The benefits of LMWH in cancer might at least in part, be independent from its anti-coagulant activities, but may still be partially dependent on its anti-coagulant activities.

Antithrombotics in thrombosis and cancer

2005 ◽  
Vol 25 (04) ◽  
pp. 380-386 ◽  
Author(s):  
S. A. Mousa
Keyword(s):  
Molecular Weight ◽  
Growth Factor ◽  
Cancer Patients ◽  
Tissue Factor ◽  
Tumour Growth ◽  
Coagulation Cascade ◽  
Low Molecular Weight ◽  
Angiogenic Growth Factors ◽  
Tumour Metastasis ◽  
The Impact

SummaryMany cancer patients have a hypercoagulable state, with recurrent thrombosis due to the impact of cancer cells and chemotherapy or radiotherapy on the coagulation cascade. Studies have demonstrated that unfractionated heparin (UFH) or its low molecular weight fractions interfere with various processes involved in tumour growth and metastasis. These include fibrin formation; binding of heparin to angiogenic growth factors, such as basic fibroblast growth factor (FGF2) and vascular endothelial growth factor (VEGF); modulation of tissue factor; and perhaps other more important modulatory mechanisms, such as enhanced tissue factor pathway inhibitor (TFPI) release and inhibition of various matrix-degrading enzymes. Clinical trials have suggested a clinically relevant effect of low molecular weight heparin (LMWH), as compared to UFH, on the survival of cancer patients with deep vein thrombosis. Similarly, the impact of warfarin on the survival of cancer patients with thromboembolic disorders was demonstrated. Studies from our laboratory demonstrated a significant role for LMWH, warfarin, anti-VIIa, and LMWH-releasable TFPI on the regulation of angiogenesis, tumour growth, and tumour metastasis. Thus, modulation of tissue factor/VIIa non-coagulant activities by LMWH, warfarin, anti-VIIa, or TFPI might be a useful therapeutic method for the inhibition of angiogenesis associated with human tumour growth and metastasis. Additionally, antiplatelet drugs could have an impact on tumour metastasis, and the combination of antiplatelets and anticoagulants at adjusted doses might provide greater benefits to cancer patients.

scholarly journals Low Molecular Weight Procyanidins from Grape Seeds Enhance the Impact of 5-Fluorouracil Chemotherapy on Caco-2 Human Colon Cancer Cells

PLoS ONE ◽  
2014 ◽  
Vol 9 (6) ◽  
pp. e98921 ◽  
Author(s):  
Ker Y. Cheah ◽  
Gordon S. Howarth ◽  
Keren A. Bindon ◽  
James A. Kennedy ◽  
Susan E. P. Bastian
Keyword(s):  
Molecular Weight ◽  
Colon Cancer ◽  
Cancer Cells ◽  
Human Colon ◽  
Low Molecular Weight ◽  
Colon Cancer Cells ◽  
Grape Seeds ◽  
Human Colon Cancer ◽  
The Impact ◽  
Human Colon Cancer Cells

Sa1963 Low Molecular Weight Procyanidins From Grape Seeds Enhance the Impact of 5-Fluorouracil Chemotherapy on Colon Cancer Cells

2014 ◽  
Vol 146 (5) ◽  
pp. S-341 ◽  
Author(s):  
Ker Y. Cheah ◽  
Gordon S. Howarth ◽  
Keren A. Bindon ◽  
James A. Kennedy ◽  
Suzanne Mashtoub ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Colon Cancer ◽  
Cancer Cells ◽  
Low Molecular Weight ◽  
Colon Cancer Cells ◽  
Grape Seeds ◽  
The Impact

scholarly journals Are All Low Molecular Weight Heparins Equivalent in the Management of Venous Thromboembolism?

2007 ◽  
Vol 14 (4) ◽  
pp. 385-392 ◽  
Author(s):  
Jawed Fareed ◽  
Walter Jeske ◽  
Daniel Fareed ◽  
Melaine Clark ◽  
Rakesh Wahi ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Clinical Trials ◽  
Venous Thromboembolism ◽  
Unfractionated Heparin ◽  
Low Molecular Weight Heparin ◽  
Randomized Clinical Trials ◽  
Safety Data ◽  
Low Molecular Weight ◽  
Efficacy And Safety ◽  
Low Molecular Weight Heparins

Low molecular weight heparins are replacing unfractionated heparin in a number of clinical indications because of their improved subcutaneous bioavailability and more predictable antithrombotic response. Clinical trials have demonstrated that low molecular weight heparins are at least as safe and effective as unfractionated heparin for the initial treatment of venous thromboembolism, and unfractionated heparin and warfarin for primary and secondary thromboprophylaxis. The mechanism behind the antithrombotic action of low molecular weight heparins is not fully understood but is likely to involve inhibition of coagulation factors Xa and IIa (thrombin), release of tissue-factor-pathway inhibitor, and inhibition of thrombin activatable fibrinolytic inhibitor. Different low molecular weight heparins have been shown to have various effects on coagulation parameters. Seven low molecular weight heparins are currently marketed worldwide, each demonstrated distinct chemical entities with unique pharmacokinetic and pharmacodynamic profiles. Each low molecular weight heparin is approved for specific indications based on the available efficacy and safety data for that product. The relative efficacy and safety of the low molecular weight heparins are unclear because there have been very few direct comparisons in randomized clinical trials. While recommending low molecular weight heparins for the prevention and treatment of venous thromboembolism, clinical guidelines have not specified individual agents. National and international organizations recognize that low molecular weight heparins are distinct entities and that they should not be used interchangeably in clinical practice. Each low molecular weight heparin should be used at the recommended dose when efficacy and safety data exist for the condition being treated. When these data are not available, the dosing and administration of low molecular weight heparins must be adapted from existing data and recommendations.

Do Heparins Do More than Just Treat Thrombosis? The Influence of Heparins on Cancer Spread

1999 ◽  
Vol 82 (08) ◽  
pp. 947-952 ◽  
Author(s):  
Rohan Hettiarachchi ◽  
Susanne Smorenburg ◽  
Jeffrey Ginsberg ◽  
Mark Levine ◽  
Martin Prins ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Clinical Trials ◽  
Venous Thromboembolism ◽  
Beneficial Effect ◽  
Cancer Patients ◽  
Treatment Effect ◽  
Initial Treatment ◽  
Randomized Clinical Trials ◽  
Meta Analysis ◽  
Low Molecular Weight

IntroductionThe influence of unfractionated heparin (UFH) and other anticoagulants on the spread of cancer has been reported since the early 1960s.1 However, clinical studies investigating the use of heparins in cancer patients have not produced consistent results.2 Intravenous, adjusted-dose UFH for 5 to 10 days has been the standard initial treatment for venous thrombosis. More recently, subcutaneous, fixed-dose, low molecular weight heparins (LMWHs), which are fractions of the parent compound, have been shown to be safe and effective alternatives to UFH in the initial treatment for venous thromboembolism.3-5 In one of our randomized clinical trials comparing LMWH and UFH in the initial treatment of deep vein thrombosis (DVT), we observed an unexpected difference in 6-month mortality among cancer patients in favor of LMWH, which could not be attributed to a difference in the incidence of thrombotic or bleeding complications.6 A similar observation in favor of LMWH was reported in a subsequent study and in a meta-analysis of trials.7,8 The number of cancer patients included in these studies was small, and adjustment of the observed effect for the baseline characteristics of the cancer patients was not possible. However, these findings suggested an inhibitory effect of LMWH on tumor growth or metastasis, which is less apparent or absent for UFH, resulting in a beneficial effect on the survival of cancer patients. This hypothesis is supported by the observations, in experimental studies, that LMWH and low molecular weight heparan sulfate, in comparison to UFH, effectively suppressed angiogenesis, a process necessary for tumor growth and metastasis.9,10 On the other hand, animal studies that investigated the effect of chemically-modified heparins on the spread of cancer did not detect a superior anti-tumor effect of LMWH compared to UFH; both were found to inhibit metastasis.11,12 To date, the effect of LMWH on cancer survival in humans has not been investigated as a primary objective. If a consistent and beneficial effect of LMWH on mortality is indeed present, such a study would be warranted.We performed a meta-analysis of all available randomized clinical trials where LMWH was compared with UFH in the treatment of venous thromboembolism (VTE) to estimate the crude treatment effect of LMWH on mortality in cancer patients compared to UFH. Subsequently, we adjusted this treatment effect for age, gender, and primary malignancy site by reanalyzing data from three of those trials.3-5 This effect was further adjusted for other prognostic factors, including cancer histology, tumor stage, presence of metastases, duration of cancer, and concomitant use of cancer treatment, by analyzing individual patient data from the largest randomized trial.5

scholarly journals Maximal Strength Training for Breast Cancer Patients Undergoing Adjuvant Treatment. Doctoral Thesis

2021 ◽  
Author(s):  
◽  
Rūdolfs Cešeiko ◽  
Keyword(s):  
Breast Cancer ◽  
Clinical Trials ◽  
Muscle Strength ◽  
Cancer Treatment ◽  
Strength Training ◽  
Cancer Patients ◽  
Adjuvant Treatment ◽  
Primary Therapy ◽  
Anti Cancer ◽  
The Impact

Objective. Breast cancer (BC) is the most frequently diagnosed type of cancer among women, with more than 2 million new cases and over 600 000 deaths annually (Bray et al., 2018), and its global incidence is steadily rising. BC patients through the cancer continuum experience complex health and psychosocial challenges. BC and anti-cancer treatment accompanied by an inactive lifestyle may further impair muscle strength and muscle force development characteristics. Historically, patients diagnosed with cancer were advises to rest and avoid vigorous activity following their diagnosis, but this dogma has changed markedly over the last 20 years as exercise oncology intervention studies have gained broad acceptance and acknowledgment. Strength training can optimally affect muscles and increased muscle strength may contribute to participation in daily activities, thus potentially improving the health-related quality of life (HRQoL). However, the optimal type, intensity and frequency of strength training, as a part of cancer care, that will most enhance muscle strength during anti-cancer treatment is yet unknown. Christensen et al. (Christensen et al., 2014) investigated newly confirmed (breast, gastric, colorectal, lung and pancreas) cancer patients and concluded that these patients had 0.9 kg lower muscle mass compared with healthy controls even before the initiation of anti-cancer treatment. Furthermore, during adjuvant chemotherapy, BC patients lost 1.3 kg lean body mass (LBM), and continued to lose LBM after therapy was completed. Ultimately, BC survivors evaluated after completion of primary therapy displayed 20–30% lower muscle strength compared with healthy counterparts. Most physical activity interventions for BC patients combine aerobic endurance training with strength training and diverse relaxation therapies, hence making it more complicated to evaluate the impact of training type. There has been a limited number of well-defined clinical trials on BC patients that include higher intensity strength training, moreover when intervention is administered during adjuvant treatment. Training intensities vary substantially across cancer studies ranging from 25–80% of one-repetition maximum (1RM), although, it has been documented that higher training intensities yield greater strength gains in young healthy individuals (Campos et al., 2002). Similarly, greater gains in muscle strength are documented with increasing intensity for cancer patients, however, these patients are likely to have some improvement even at low training intensities (Fairman et al., 2017). The common consent from clinical trials when strength training interventions were applied for cancer patients states that training programs were well tolerated, they are safe, feasible and showed strength improvements that led to improved physical functioning and improved HRQoL (Segal et al., 2003), (De Backer et al., 2007), (Battaglini et al., 2014). Recognizing that training intensity during strength training is a key factor to improve maximal muscular strength and strength related characteristics. Therefore, well-defined training methods with high intensity could also be preferable to induce greater physiological adaptations, thus contribute to faster recovery from specific cancer treatment and enhancing the completion of prescribed anti-cancer treatment.

scholarly journals Maximal Strength Training for Breast Cancer Patients Undergoing Adjuvant Treatment. Summary of the Doctoral Thesis

2021 ◽  
Author(s):  
◽  
Rūdolfs Cešeiko ◽  
Keyword(s):  
Breast Cancer ◽  
Clinical Trials ◽  
Muscle Strength ◽  
Cancer Treatment ◽  
Strength Training ◽  
Cancer Patients ◽  
Adjuvant Treatment ◽  
Primary Therapy ◽  
Anti Cancer ◽  
The Impact

Objective. Breast cancer (BC) is the most frequently diagnosed type of cancer among women, with more than 2 million new cases and over 600 000 deaths annually (Bray et al., 2018), and its global incidence is steadily rising. BC patients through the cancer continuum experience complex health and psychosocial challenges. BC and anti-cancer treatment accompanied by an inactive lifestyle may further impair muscle strength and muscle force development characteristics. Historically, patients diagnosed with cancer were advises to rest and avoid vigorous activity following their diagnosis, but this dogma has changed markedly over the last 20 years as exercise oncology intervention studies have gained broad acceptance and acknowledgment. Strength training can optimally affect muscles and increased muscle strength may contribute to participation in daily activities, thus potentially improving the health-related quality of life (HRQoL). However, the optimal type, intensity and frequency of strength training, as a part of cancer care, that will most enhance muscle strength during anti-cancer treatment is yet unknown. Christensen et al. (Christensen et al., 2014) investigated newly confirmed (breast, gastric, colorectal, lung and pancreas) cancer patients and concluded that these patients had 0.9 kg lower muscle mass compared with healthy controls even before the initiation of anti-cancer treatment. Furthermore, during adjuvant chemotherapy, BC patients lost 1.3 kg lean body mass (LBM), and continued to lose LBM after therapy was completed. Ultimately, BC survivors evaluated after completion of primary therapy displayed 20–30% lower muscle strength compared with healthy counterparts. Most physical activity interventions for BC patients combine aerobic endurance training with strength training and diverse relaxation therapies, hence making it more complicated to evaluate the impact of training type. There has been a limited number of well-defined clinical trials on BC patients that include higher intensity strength training, moreover when intervention is administered during adjuvant treatment. Training intensities vary substantially across cancer studies ranging from 25–80% of one-repetition maximum (1RM), although, it has been documented that higher training intensities yield greater strength gains in young healthy individuals (Campos et al., 2002). Similarly, greater gains in muscle strength are documented with increasing intensity for cancer patients, however, these patients are likely to have some improvement even at low training intensities (Fairman et al., 2017). The common consent from clinical trials when strength training interventions were applied for cancer patients states that training programs were well tolerated, they are safe, feasible and showed strength improvements that led to improved physical functioning and improved HRQoL (Segal et al., 2003), (De Backer et al., 2007), (Battaglini et al., 2014). Recognizing that training intensity during strength training is a key factor to improve maximal muscular strength and strength related characteristics. Therefore, well-defined training methods with high intensity could also be preferable to induce greater physiological adaptations, thus contribute to faster recovery from specific cancer treatment and enhancing the completion of prescribed anti-cancer treatment.

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