AN ORAL ANGIOGENESIS INHIBITOR

Oral Cancer Drug Shows Promise

May be useful for long-term therapy

AN ORAL ANGIOGENESIS INHIBITOR slowed tumor progression in mice, researchers report. Because the drug can be taken orally and shows no toxic effects in various models of the disease, it may be useful as a preventative therapy for people who are in remission from cancer, according to researchers at Harvard University.

The drug, lodamin, is a new version of an angio-genesis inhibitor developed almost 20 years ago but abandoned due to its neurotoxic effects in humans. Researchers led by Ofra Benny, PhD, of Children'S Hospital Boston, reformulated the drug using nanotechnology, encasing it in micelles made from two small polymers. The study, published in the July issue of Nature Biotechnology, showed that the drug can be ingested and absorbed by the intestines and accumulates selectively in tumors. (Benny O, Fainaru O, Adini A, et al. An orally delivered small-molecule formulation with antiangiogenic and anti-cancer activity. Nat Biotechnol. 2008;26(7):799-807.)

The researchers tested the drug in a liver metastasis model in which they injected the mice with tumor cells. By day 20, four of the seven control mice were dead, while all seven of the lodamin-treated mice were still alive. In addition, while the control mice showed massive macrometastasis on their livers, only one of the treated mice had cancer nodules on its liver.

"These results suggest that lodamin can prevent the development of metastasis in the liver," the study authors wrote. "Importantly, this property of the polymeric micelles might be used for the development of other antiangiogenic or anticancer drugs that target liver metastasis."

After tracking the biodistribution and tissue uptake of the drug by treating mice with fluorescently labeled micelles for three days, the researchers found that a high concentration accumulated in the stomach and small intestine, with the highest levels in the liver. No micelles were detected in the brain. In tumor-bearing mice, the highest uptake of micelles was detected in tumor cells.

In another tumor model, murine melanoma, a lodamin dosage of 15 mg/kg per day for 13 days reduced tumor volume by 77%; no side effects were detected. When the dosage was increased to 30 mg/kg per day and 60 mg/kg every other day, however, some of the mice experienced weight loss.

We believe that in angiogenesis, it is very important to have an oral drug, since in the future people would need drugs which can be given chronically to treat small tumors in a non-angiogenic/dormant state.

-Ofra Benny, PhD, Children's Hospital Boston

The drug on which lodamin is based, TNP-470, was originally developed under the direction of the late Judah Folkman, MD, in the same lab where the current work is taking place. To test whether this version of the drug causes neurotoxicity, the team had the mice cross a narrow beam. Mice injected with the free TNP-470 showed a 50% increase in foot-slip errors, while the lodamin-treated mice performed like untreated control mice.

"The work of lodamin opens up a way of using the same approach for other non-soluble, small-molecule drugs," Dr. Benny said in an e-mail to PFQ. "We believe that in angiogenesis, it is very important to have an oral drug, since in the future people would need drugs which can be given chronically to treat small tumors in a non-angiogenic/dormant state, which is actually not a dangerous stage."

Dr. Benny said that the team is now looking to test lodamin in animal models of age-related macular degeneration and arthritis. They will also study the effect of the drug on metastasis development in different organs and the use of lodamin in combination with other drugs and radiation therapy.