JERUSALEM ¿ Mammalian heparanase, a unique inhibitor of metastases in patients with cancer, has been cloned and expressed after nearly two decades of trying.

An report from an Israeli team, which is featured on the cover of Nature Medicine, and another report by an Australian team both appear in the July issue of that publication showing, contrary to expectations, there is only one heparanase, regardless of tissue source of the gene and in contrast to the many proteases discovered for passing through plasma membranes.

The Israeli group, led by Israel Vlodavsky, head of the Tumor Biology Research Unit in the department of oncology of the Hadassah Medical Center-Hebrew University, EinKerem, Jerusalem, and Iris Pecker, from the young biotech firm Insight Ltd. in Rehovot, Israel, showed that cancer cells transfected with heparanase cDNA become highly metastatic; adenocarcinoma of human colon overexpress the enzyme; and that only cancerous, and not normal epithelium, immunostains for heparanase.

The Australians, led by Christopher Parish of the John Curtin School of Medical Research in Canberra, Australia, partnering with Progen Ltd., of Brisbane, found that tumor cell invasiveness correlates with the activity of the heparanase gene.

The new understanding emerging is that the lone heparanase is the key enzyme allowing tumor cells to pass through the extracellular matrix and also to breach the basement membranes that surround blood vessels. Thus, inhibiting this single enzyme would prevent cancer cell invasion of new (secondary tumor) sites and prevent the neoangiogenesis that tumors need to allow their rapid growth.

Both the Israelis and the Australians are working on heparanase inhibitors.

Progen said a Phase I clinical trial of its PI-88 showed the inhibitor is well tolerated in healthy volunteers for the short periods needed.

InSight¿s first patent, ¿Polynucleotide encoding a small polypeptide having heparanase activity,¿ filed in Septem ber 1997, was allowed first by the U.S. Patent and Trade mark Office, and soon will be published.

¿Our small-molecule heparanase inhibitors, discovered by our proprietary high-throughput screening assays, are very well defined, very stable, and are being used for our trials for inflammatory disease as well as metastatic cancers,¿ said Dror Melamed, molecular biologist and vice president of operations at InSight.