These in vivo and in vitro findings may help guide the future clinical development of Amplimexon, which recently entered a phase I/II study in combination with gemcitabine (Eli Lilly’s Gemzar) in the treatment of patients with previously untreated pancreatic adenocarcinoma. These new data suggest that the drug may have broader utility than previously thought.
The active ingredient in Amplimexon is imexon, a compound which has previously shown activity against a variety of human cancer types in cell- based and animal studies, including melanoma, myeloma and pancreatic adenocarcinoma. Previous work had suggested that imexon might augment the effectiveness of other cancer drugs by causing the accumulation of toxic free radicals inside rapidly dividing cells such as cancer cells. However, this mechanism does not adequately explain the significant synergies observed between imexon and a certain class of cancer drugs known as antimetabolites.
One such drug is gemcitabine, which is used as first line therapy in pancreatic cancer that cannot be treated surgically. Advanced pancreatic cancer is often resistant to gemcitabine and response rates are relatively low. Experiments in animals implanted with human pancreas tumor cells had suggested that the combined use of imexon and gemcitabine was much more effective at slowing tumor growth and causing tumor shrinkage than either drug alone, even causing regression in tumors resistant to each individual drug.
Arizona researchers have found evidence to indicate imexon possesses additional biological and biochemical properties that may explain these unexpected positive findings. Findings suggest imexon is an inhibitor of the processes by which a cell divides, causing cells to accumulate in a particular phase of the cell cycle during which they are highly susceptible to gemcitabine therapy.
Furthermore, it appears imexon directly targets an enzyme called ribonucleotide reductase (RNR) which is a necessary component of the pathway to DNA synthesis. RNR is also a target for gemcitabine itself and the combination of the two drugs is more effective than either drug alone at inhibiting this key enzyme.
Additional clinical studies are now planned designed to prove the clinical utility of the Amplimexon/gemcitabine combination in pancreatic cancer.