Jul 10 2004
Ohio researchers have used a recently developed anti-inflammatory drug as a starting point to construct a possible new, targeted anti-cancer agent. The new agent works by triggering cancer cells to self-destruct.
The agent is now undergoing laboratory testing by the National Cancer Institute’s (NCI) Rapid Access to Intervention Development (RAID) program.
The potential new drug was developed by researchers at The Ohio State University College of Pharmacy and the OSU Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute. Presently, the agent is known as OSU-03012. The study is published in the June 15 issue of the journal Cancer Research.
“This new agent works by inhibiting a fundamental signaling point in cancer cells, making it potentially effective in a wide range of cancer types,” says study leader Ching-Shih Chen, professor of pharmacy and a researcher with OSU’s Comprehensive Cancer Center.
“We also have evidence that it may sensitize leukemia, and breast and lung cancers to conventional chemotherapy.”
The new agent is based on the drug celecoxib (Celebrexâ), a nonsteroidal anti-inflammatory drug, or NSAID. Like many NSAIDs, celecoxib also reduces the risk of colorectal cancer when taken regularly.
Scientists knew from the start that celecoxib helps control inflammation by inhibiting an enzyme known as cyclooxygenase-2 (COX-2). But they couldn’t explain the drug’s modest anti-cancer activity.
Past work led by Chen provided the answer.
“We found that celecoxib’s ability to cause cell death and to control inflammation were two different pharmacological properties, and that the two properties could be separated,” Chen says. This work was published in the Journal of the National Cancer Institute.
Chen and his colleagues then showed that celecoxib inhibited a molecule known as Akt.
Chen describes Akt as an important molecular switch that transmits information from the cell surface down into the cell to interact with a variety of target molecules. He and colleagues further found that the blocking of Akt by celecoxib in cancer cells triggered programmed cell death, a process also known as apoptosis.
For this study, Chen and his colleagues used molecular-modeling methods and computational chemistry to alter celecoxib’s basic molecular structure in ways calculated to maximize its Akt-blocking and cell-death inducing activities.
This work generated a series of derivative molecules, all of which were far different in structure from celecoxib. Two of these proved to be 30 to 50 times more potent than celecoxib in inducing programmed cell death in cancer cells growing in the laboratory tests.
One of the derivatives, OSU 03012, is now undergoing toxicological and pharmacological testing by the NCI’s RAID program. Data from these tests will help move the agent forward into human testing in a phase I clinical trial, probably within one to two years.