Use of heparin derivatives in several cancer types revealed that anticoagulant therapies have a beneficiary side effect: delay of tumor progression. Since there are no data on human melanoma, we have analyzed the effect of heparins in preclinical models. Neither unfractionated heparin (UFH), nor its low molecular weight derivative (LMWH) influenced in vitro or in vivo growth of HT168-M1 human melanoma cells. However, heparins significantly inhibited lung colony formation and liver metastasis development in the concentration range of 20-200 IU/kg, whereas recombinant hirudin was ineffective. The antimetastatic effect was due to an early (5-60 min) inhibition of tumor cell arrest in the lung microvasculature. Analysis of the molecular mechanism of the antimetastatic effect of heparins indicated a specific inhibition of tumor cell migration and matrix invasion. The presented experimental data suggest that heparins have specific antimetastatic effect in the case of human melanoma, which is independent from the coagulation cascade.
Recombinant human erythropoietin (rHuEPO) is widely used for correction of hemoglobin level in cancer patients. However, apart from hematopoiesis, rHuEPO reportedly has an effect on endothelial cells. We describe here how rHuEPOA can modulate tumor vasculature in human squamous cell (A431) and colorectal carcinoma (HT25) xenograft models. In vivo rHuEPO treatment of xenografts at human-equivalent dose significantly increased the proliferation index of the tumor-associated endothelial cells and the size of CD31-positive intratumoral blood vessels, whereas the pericyte coverage became fragmented. Moreover, rHuEPO administration resulted in decreased expression of vascular endothelial growth factor both by cancer cells and tumor stroma, measured by quantitative PCR. Due to the morphologic alterations in tumoral microvessels, DNA-binding agents (Hoechst and Doxorubicin) labeled significantly larger areas in the tumor mass. Furthermore, rHuEPO treatment led to a significantly improved efficacy of 5-fluorouracil (5-FU) chemotherapy in the case of both tumor xenografts. Meanwhile, rHuEPO had no effect on the in vitro proliferation of erythropoietin receptor-positive tumor cells, and did not interfere with the effects of 5-FU either. These data reveal a new effect of rHuEPO administration: remodeling tumoral microvessels, suppressing vascular endothelial growth factor expression, thereby augmenting antitumor effects of a cancer drug, 5-FU, even in erythropoietin receptor-positive human cancer xenografts. (Cancer Res 2005; 65(16): 7186-93)
rHuEPOalpha treatment may modulate the efficacy of cancer radiotherapy not only by reducing systemic hypoxia and tumoral HIF-1alpha expression, but also by destroying tumoral vessels.
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