Oncogene Blockers Near Clinical Trials

A completely new approach to cancer therapy, targeting the oncogene products which become activated when cells become neoplastic, has been presented at the American Association for Cancer Research in Toronto, Canada. Small-molecule non-peptide inhibitors of the ras oncogene which are being developed by Merck & Co, a pioneer in the field, should be in clinical trials "within the next 12 to 18 months," according to Allen Oliff, executive director of cancer research at the company.

The new compounds act at the level of ras by inhibiting the enzyme farnesyl transferase (FTase). This enzyme catalyzes farnesylation of the oncogene product, Ras, which is a required step for its malignant transforming activity. This farnesylation step is a lipid post-translational modification that allows the Ras oncoprotein to localize in the plasma membrane of a cell, where it plays a pivotal role in growth factor signalling and malignancy.

In vitro experiments carried out by Said Sebti and colleagues at the University of Pittsburgh have revealed that inhibitors of FTase can block the stimulation by platelet-derived growth factor (PDGF) of mitogen-activated protein kinase and DNA synthesis, as well as PDGF-induced tyrosine phosphorylation of the PDGF receptor and its association with a key enzyme in a secondary messenger system in growth factor signaling of cell division, phosphatidyl inositol-3-kinase.