Unfractionated heparin and it derivatives are known to produce pleotropic effects including the anticoagulant, anti-inflammatory and antitumor actions. Preclinical evidence suggests that heparins have an effect on tumor progression independent of their anticoagulant activity. Heparin and low molecular weight heparin have also been shown to exhibit interactions with growth factors and other cellular receptors. Recently an ultra low molecular weight heparin namely, semuloparin has also been found to be effective in the management of cancer associated thrombosis (Save ONCO trial). This study was designed to investigate whether heparin and its derivatives are able to inhibit tumor growth in a Lewis Lung carcinoma model.
Female C57BL/6 mice were obtained at 6–8 weeks of age and were implanted with 5×105 LN7 tumor cells by dorsal subcutaneous injection in the upper back. When tumors were initially palpable, at 7–10 days of growth, mice were treated with subcutaneous injections of heparin, a low molecular weight heparin (LMWH), namely enoxaparin, an ultra LMWH, semuloparin or saline, daily for two weeks at approximately 1 cm away from the tumor growth, in a dose range of 1.0 – 0.25 mg/kg. After the treatment period, animals were sacrificed and the spleens and tumors were removed and tumor weight, tumor volume, spleen weight and spleen size were measured. Blood samples were drawn through heart puncture for ex vivo analysis. VEGF levels were measured using a commercially available ELISA method.
At the 1.0 and 0.5 mg/kg dosages, both enoxaparin (p<0.01) and semuloparin (p<0.01) showed a decrease in tumor volume compared to the saline control animals. At the 1.0 mg/kg dosage although heparin was effective in reducing the tumor size, the mortality was higher in this group due to bleeding. At 0.5 mg/kg heparin was not different from the saline control in terms of reducing tumor growth. In addition, at a dosage of 0.25 mg/kg, only semuloparin showed a significant difference in reducing the tumor size in comparison to saline control (p<0.01). Similar results were observed for the tumor weight. There were no significant differences noted in spleen weight or spleen size among these agents. The mortality rates in the mice treated with enoxaparin and semuloparin were relatively lower (<10%) and were comparable between the two groups. Ex vivo analysis of blood showed a significant difference in the VEGF levels in the semuloparin group in comparison to enoxaparin and heparin.
These studies suggest that heparin and its derivatives are capable of inhibiting tumor growth in a dose dependent manner. Enoxaparin and semuloparin are more effective at reducing tumor growth compared to heparin. In addition, both the enoxaparin and semuloparin were safer than heparin at the 1.0 and 0.5 mg dosages as bleeding was observed in the heparin treated animals. Semuloparin downregulated the VEGF levels in comparison to the other groups suggesting that this mechanism potentially plays a role in the control of the tumor growth. Reported clinical studies have shown that semuloparin is safer and effective for the prevention of venous thromboembolism in cancer patients and compares favorably to enoxaparin in terms of antithrombotic effect and safety profile. Therefore, semuloparin may be a better alternate for the management of cancer associated thrombosis.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.