The Problem of Multi-Drug Resistance

For years it has been known in the medical and pharmaceutical industries that the characteristic that results in the majority of cancer deaths is multi-drug resistance (MDR) to chemotherapy in relapsed/refractory cancer patients. MDR results in as many as five hundred thousand deaths from cancer annually in the United States alone. Clearly, this is one of the largest unmet medical needs for a life threatening disease, with an annual market potential for an effective treatment of MDR in the multiple billions of dollars.

Despite years of costly innovative research and clinical investigation conducted by some of the most reputable cancer centers and pharmaceutical companies worldwide, no drug or treatment protocol has been approved that safely and effectively sustains modulation of multidrug resistance cancer. It may require as much as 100 times the acceptable levels of chemotherapy agents to effectively treat patients with MDR in the absence of an MDR Modulator. To date, no drug is available to treat relapsed/refractory cancer patients that are drug resistant to chemotherapy.

Tumor of average detectable size contains hundreds of millions of cells, some are likely to be drug resistant.

Treatment with chemotherapy (even combinations) may result in response or remission, yet the drug resistant cells and their progeny continue to multiply.

Eventually, drug resistant cancer cells dominate and continue to multiply, resulting in death.

Mechanisms that promote MDR in cancer cells include multidrug resistance casually associated with glutathione-s-transferase and topoisomerase I/II isoenzymes as well as more intensively studied MDR-1, MRP-1, LRP and ABCG2 proteins. The P-glycoprotein (Pgp) pump and MDR-1 encoded membrane, is one of the most prevalent and well documented causes of MDR. The Pgp pump, a member of the super family known as ATP-binding cassettes (ABC), acts as an efflux transporter that lowers intracellular concentration of multiple chemotherapeutic agents, thus creating MDR. What has been needed to solve the MDR problem is an MDR Modulator that inhibits the MDR pumps, especially the Pgp and MRP-1 pumps.