MNTA cancer drug
thanks for the link. much of the article is dedicated to use of anticoagulants to prevent thrombosis in cancer patients (cancer induces a hypercoaguable state). here is the relevant snippet on the direct anticancer effect of heparins
Anticoagulants may be associated with increased survival in cancer patients
Three major studies have indicated that the LMWHs may be associated with a survival benefit in cancer patients that could not be directly linked to a reduction in VTE incidence [91-93]. In the Malignancy and Low Molecular Weight-Heparin Therapy (MALT) trial, cancer patients were randomly assigned to 6-weeks of either the LMWH nadroparin (n = 148) or placebo (n = 154). At 12 months the overall HR for death was 0.75 (95% CI: 0.59-0.96) with a median survival of 8.0 months in the nadroparin group compared with 6.6 months in the placebo group [91]. Similarly, The Fragmin Advanced Malignancy Outcome Study (FAMOUS) compared the LMWH dalteparin given for 1-year with placebo in cancer patients. The Kaplan-Meier survival estimates for 1, 2, and 3 years after randomization were not different between the dalteparin and placebo groups (p = 0.19). However, in an analysis not planned a priori, a sub-group of patients who were alive at 17 months, experienced significantly improved survival estimates at 2- and 3-years following randomization with dalteparin versus placebo (78% vs. 55% and 60% vs. 36%, respectively; p = 0.03) with no increase in major bleeding rates [92]. Notably, these effects were observed long after dalteparin was discontinued, suggesting the survival benefit is not dependent on VTE prophylaxis.In the CLOT trial, over 600 patients with cancer and VTE were randomized to receive 6-months of warfarin or dalteparin therapy. A survival benefit for LMWH over warfarin was observed in patients with non-metastatic cancer, with a 20% mortality rate in the dalteparin group compared with 36% with warfarin (HR 0.50; 95% CI: 0.27-0.95; p = 0.03). However this benefit was not maintained in patients with metastatic cancer (72% vs. 69%, respectively; HR 1.1; 95% CI: 0.87-1.4; p = 0.46) [93].Although some studies have suggested that warfarin may also improve survival in cancer patients [94,95] and reduce the incidence of cancer [96], a meta-analysis of 11 studies comparing mortality with the LMWHs versus warfarin demonstrated that although the LMWHs increased survival (RR 0.877; 95% CI: 0.789-0.975; p = 0.015) warfarin did not (RR 0.942; 95% CI: 0.854-1.040; p = 0.239) [32]. Furthermore, patients receiving warfarin therapy also had a significant increase in the risk of major bleeding (RR 2.979; 95% CI: 2.134-4.157; p < 0.0001) whereas those receiving LMWH did not (RR 1.678; 95% CI: 0.861-2.269, p = 0.128). In a systematic review of the literature, heparin (UFH or LMWH) was associated with a survival benefit in cancer patients (HR 0.77, 95% CI 0.65-0.91) without significantly increasing the risk of bleeding (RR 1.78, 95% CI 0.73-4.38) [97]. When analyzed by subgroups however, a statistically significant survival benefit was observed in patients with limited small-cell lung cancer (SCLC) (HR 0.56, 95% CI 0.38-0.83), but was not seen in patients with more extensive SCLC (HR 0.80, 95% CI 0.60-1.06) or patients with advanced disease (HR 0.84, 95% CI 0.68-1.03) [97].Thus it appears that the LMWHs may be associated with improved survival in certain cancer populations. However, more studies are needed to fully characterize this effect and how it is affected by different cancer locations, types, and disease stage. Accordingly, current evidence-based guidelines delineating appropriate thromboprophylaxis and VTE-treatment in cancer patients do not recommend the use of primary thromboprophylaxis to try to improve survival in cancer patients, and use of a LMWH for this indication would be off-label [1,17,19].Findings suggest that the improvements in survival seen with the LMWHs in cancer patients do not simply result from a decrease in the incidence of VTE, but also from potential anti-neoplastic properties of heparins. Heparin and its derivatives possess mucopolysaccharide chains similar to cell-surface and extra-cellular matrix molecules, raising the possibility that UFH and LMWHs can modulate how cells interact with their environment, enzymes, and cell-signaling molecules, and so affect malignant cell growth [98]. In vivo evidence suggests that the anti-metastatic effects of heparins depend upon P-selectin-mediated binding via their polysaccharide chains rather than their antithrombotic activity [99]. Accordingly fondaparinux, which lacks a polysaccharide chain, did not inhibit metastasis at clinically relevant anticoagulation levels in this model [99]. Similarly, UFH, LMWHs and oligosaccharide truncates of heparin have been shown to inhibit tumor growth and metastasis in vivo [100].Heparin and oligosaccharide truncates of heparin have also been shown to inhibit angiogenesis [101]. Studies have demonstrated UFH and LMWH have dose-dependent antiangiogenic effects that are mediated via release of endothelial tissue factor pathway inhibitor, which are independent of their antithrombotic activity [102]. Furthermore, heparins can directly affect the immune system by their inhibitory effects on extravasation of leukocytes and the complement system, or by enhancing the susceptibility of cancer cells to immunologic attacks [103]. Consequently, it is likely the proposed anti-neoplastic effects of heparin and the LMWHs are a combination of direct anti-neoplastic, antiangiogenetic, and immunomodulatory effects, as well as indirect effects resulting from their pleiotropic action on the coagulation system.Each LMWH has a particular structural profile which in turns gives it specific pharmacokinetic and pharmacodynamic properties [104,105]. Structural differences between the LMWHs such as in the molecular weight, molecule length, end-group composition, carboxyl-to-sulfate group ratio and the proportion of anti-Xa binding domains have been shown to affect the biological activity of the resulting molecule [104,105]. It is possible therefore that the LMWHs possess different anti-metastatic properties to one another. However, it is unclear at present to what extent the structural heterogeneity between the LMWHs translates into clinical differences in the drug's anti-metastatic effect. Current research is investigating separating the anticoagulant and anti-metastatic properties of heparin molecules for use in cancer patients [106].The complex mechanisms associated with improvements in survival of cancer patients treated with heparins are of relevance to the new generation of oral anticoagulants which are under development [107]. In an attempt to separate antithrombotic and bleeding effects, agents have been designed to inhibit specific proteins within the coagulation cascade. However, these new drugs lack the polypharmacological actions of the UFH and LMWHs which are thought to be involved in anti-neoplastic effects, and accordingly it is likely that they will also have concurrent reductions in their anti-neoplastic activity.
