Gentium's Defibrotide Highlighted in Two Poster Presentations at American Association for Cancer Research Annual Meeting
On Monday, April 16, 2007, from 1:00 p.m. to 5:00 p.m. (Pacific Time), Dr. Cinara Echart, Ph.D., Manager of Biological Research Laboratory at Gentium, will present a poster entitled "Modulation Of Heparanase Expression In Myeloma Tumor Cell Lines By Defibrotide: A Novel Mechanism Of Anti-Tumor Activity." (Poster session 23, Tumor Biology 21, Abstract #3100, Board #29)
Elevated heparanase expression in humans has been correlated with advanced progression and metastasis of many tumor types, including multiple myeloma (MM), where its presence may be particularly important because MM expresses high levels of heparin sulphate proteoglycan syndecan-1(CD138).
This in vitro study investigated Defibrotide's effectiveness in regulating the expression and activity of heparanase in two MM cell lines, U266 and RPMI 8226. The potential effect of Defibrotide to regulate heparanase gene expression was evaluated through real time polymerase chain reaction (RT-PCR) of cDNA prepared from the two lines of MM cells treated with Defibrotide or saline. Heparanase activity was measured in MM cells treated with Defibrotide (at 50, 100 and 150 (mu)g/ml) or saline for 24 hours by using a heparan-degrading enzyme kit. Results showed a significant down-regulation of heparanase gene expression by Defibrotide (at 150 (mu)/ml) after 24 hours of treatment (p less than 0.01) compared with saline.
Dr. Echart expounded upon these results, "These pre-clinical data suggest that Defibrotide not only has an effect in down-regulation of heparanase gene expression, but also decreases its enzymatic activity in MM cell lines. Thus, Defibrotide may suppress tumor-associated angiogenesis and tumor dissemination through suppression of heparanase with a subsequent reduction in the release of stores of growth factors from the extra-cellular matrix. This, in part, may explain Defibrotide's anti-MM activity both in vitro and in vivo."
On Tuesday, April 17, 2007, from 1:00 p.m. to 5:00 p.m. (Pacific Time), Dr. Gunther Eissner, Ph.D., Gentium's Chief of Biology, will present a poster entitled "Defibrotide: an endothelium stabilizing drug prevents angiogenesis in vitro and in vivo." (Poster session 21, Tumor Biology 29, Abstract #4627, Board #30)
The anti-angiogenic potential of Defibrotide was tested in vitro using a kit with human micro-vascular endothelial cells forming vessel structures across a layer of dermal fibroblasts. The results demonstrated that Defibrotide at concentrations corresponding to pharmacological Defibrotide blood levels (100 (mu)g/mL) reduced vessel formation, which could be confirmed by two classical in vitro angiogenesis assays (tube formation in matrigel, rat aortic ring sprouting).
In vivo, tumor angiogenesis was assessed in the murine dorsal skin-fold chamber model using the inoculation of human gastric adenocarcinoma (TMK-1) cells. Intravenous application of Defibrotide (450 mg/kg daily) significantly reduced tumor angiogenesis, as measured by micro-vascular density at day 7 (p=0.035).
The signal transduction mechanism of Defibrotide as demonstrated by Western blotting results show that Defibrotide reduces phosphorylation-activation of p70S6 kinase, which is a key target in the PI3K/Akt/mTOR signaling pathway linked to angiogenesis. Additional in vitro data show that Defibrotide does not influence proliferation of vascular, perivascular or tumor cells, and that it might selectively act through a migration and tube formation inhibition of endothelial cells.
Commenting on these pre-clinical results, Dr. Eissner stated, "Our in vivo and in vitro data suggest that while Defibrotide is known for its anti-inflammatory and endothelium-protecting function, it also inhibits (tumor) blood vessel formation. This concept is supported by RT-PCR data showing that Defibrotide significantly down-regulates heparanase expression in endothelial and tumor cells, and thus should be considered for further testing as an anticancer agent."
Laura Ferro, M.D., Gentium's president and chief executive officer, said, "These pre-clinical results are very encouraging and continue to expand our scientific knowledge of Defibrotide's multi-factorial mechanisms of action and help us to better understand its therapeutic value as a potentially powerful anticancer agent.
"We are especially pleased with the data presented at AACR as it further elucidates Defibrotide's mechanism of action and corroborates positive preliminary data from an independent Phase I/II study of Defibrotide to treat multiple myeloma in combination with melphalan, prednisone and thalidomide underway in Italy."
Gentium, S.p.A., located in Como, Italy, is a biopharmaceutical company focused on the research, discovery and development of drugs to treat and prevent a variety of vascular diseases and conditions related to cancer and cancer treatments. Defibrotide, the Company's lead product candidate, is an investigational drug that has been granted Orphan Drug status and Fast Track Designation by the U.S. Food and Drug Administration to treat Severe Veno-occlusive disease (VOD) and Orphan Medicinal Product Designation by the European Commission both to treat and to prevent VOD.
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Posted: April 2007