Kosan Biosciences Incorporated announced that 17-AAG and 5-fluorouracil (5-FU), administered in combination against human colon cancer cell lines, results in a synergistic growth inhibiting effect. According to study investigators, the combination of 17-AAG and 5-FU warrants further investigation as an anticancer therapy. Kosan and the National Cancer Institute (NCI) are collaborating to co-develop 17-AAG and other geldanamycin derivatives, and are planning to initiate Phase II monotherapy trials and Phase Ib combination trials in the second half of 2003.
Kosan evaluated the cytotoxic activity of 17-AAG and 5-FU singly and in combination against four human colon cancer cell lines. In all four cell lines, the combinations of 17-AAG and 5-FU resulted in a significantly enhanced anti-proliferative activity than demonstrated by the sum of activities of the individual drugs.
"The synergistic anti-proliferative activity of 17-AAG and 5-FU against human colon cancer cell lines is unanticipated and very exciting," stated Robert G. Johnson, Jr. Senior Vice President, Medical Affairs and Corporate Development and Chief Medical Officer at Kosan. "These data support our premise that 17-AAG sensitizes cells to the activity of many other chemotherapeutic agents."
17-AAG is a derivative of the polyketide geldanamycin. Geldanamycin and derivatives such as 17-AAG inhibit Hsp90 (heat shock protein 90). Hsp90 is a protein chaperone that binds to several sets of signaling proteins, known as "client proteins" which include the "who's who" of relevant cancer targets including protein kinases such as Bcr-Abl, Raf-1, and ErB2 as well as steroid hormone receptors and other intracellular targets. When 17-AAG binds to Hsp90, it causes dissociation and degradation of the client proteins. The pharmaco-sensitizing effects of 17-AAG with other anticancer agents have been demonstrated in preclinical models and are actively being examined.