Polysaccharide combats cancer drug resistance
a purely structural and inert role in cells may play a key role in
bringing about multidrug resistance in cancer.
Understanding the mechanisms by which tumours become resistant to a particular agent is key to identifying new drugs or combination regimens. While the problem of resistance will always be an ongoing problem for the pharmaceutical industry, new strategies and points of attack will ensure the fight against resistance will be an equal one.
In the recent study, scientists from the Medical University of South Carolina, used antagonists for this molecule to sensitise drug resistant breast cancer cells to chemotherapeutic drug treatment.
Multidrug resistance is often caused by an increase in the cell's production of proteins that transport drugs out of the cell, preventing the drugs from combating cancer. Resistance to treatment with anticancer drugs can also result from a variety of factors including individual variations in patients and somatic cell genetic differences in tumours, even those from the same tissue of origin.
In previous research Dr Bryan Toole and his coworkers, Drs. Suniti Misra and Shibnath Ghatak, of the Medical University of South Carolina, noticed that small pieces, or oligomers, of a polysaccharide called hyaluronan were able to sensitise drug-resistant breast cancer cells to several different chemotherapeutic drugs.
He believed that the polysaccharide oligomers were binding to a receptor for hyaluronan (called CD44) and preventing it from initiating a signalling cascade that would result in drug resistance.
"It is very surprising that hyaluronan is involved in drug resistance," admits Dr. Toole. "Most scientists think of hyaluronan as a structural and inert molecule. In adult tissues it plays two roles. First, it assists in tissue hydration and in biophysical properties such as resilience. Second, it forms a template to which matrix proteins attach and form important extracellular structural complexes."
Hyaluronan also accumulates around the outside of cells during disease processes such as early atherogenesis, persistent inflammation, and cancer. In recent years, however, hyaluronan has also been shown to induce signalling pathways in inflammatory, embryonic and cancer cells.
In their current Journal of Biological Chemistry paper, Dr. Toole and his colleagues report on further studies which indicate that hyaluronan increases the cellular production of a multidrug transporter protein by binding to CD44. They discovered that antagonist molecules that bind to hyaluronan and prevent it from interacting with CD44 were able to sensitise multidrug resistant breast cancer cells to chemotherapeutic drugs.
The researchers also found that increasing hyaluronan synthesis in cells increased resistance to drug treatment.
"Our work indicates that hyaluronan antagonists, for example small hyaluronan oligomers, reverse the malignant properties of cancer cells, including proliferation, invasiveness, and drug resistance," explains Dr Toole.
"Hyaluronan oligomers are non-toxic, non-immunogenic, and readily applicable to several proliferative disease processes, especially cancer. We are hoping that much lower and less toxic doses of chemotherapeutic agents can be used," he added.
With the oncology market worth an estimated $40 billion (€32 billion) in 2004 behind the cardiovascular and CNS therapy areas the prospect of a decrease in multidrug resistant cancer cases seems unlikely. These new findings suggest that existing cancer treatments may be made more effective by using hyaluronan antagonists in conjunction with existing chemotherapy.
However, according to the new Pharmacor study entitled "Non-Small-Cell Lung Cancer," the NSCLC drug market will be impacted by generic erosion when three major chemotherapy drugs go off patent.
Aventis's Taxotere patent expires in 2007 in Europe and in 2010 in the United States; Bristol-Myers Squibb's Paraplatin patent expires in 2004 in the United States; and between 2004-2010, Eli Lilly's Gemzar patent expires in all European countries and the United States.
The research appears as the "Paper of the Week" in the May 27 issue of the Journal of Biological Chemistry, an American Society for Biochemistry and Molecular Biology journal.
