Sandoz MDR Drug Shows Promise In Early Trials

It is now well established that P-glycoprotein, the product of the multidrug resistance (MDR-1) gene, is one of the key causes of resistance in a wide range of human cancers. PG is thought to act as an energy-dependent molecular efflux pump which removes chemotherapeutic agents (and other toxins) out of the cell. Drug strategies which address this are currently under evaluation, and one, Sandoz' PSC 833, is showing early promise.

Many tumor types which are resistant to chemotherapy have abnormally high levels of PG, including colorectal, liver and kidney cancer. Other studies have shown that the presence of high levels of PG may be associated with poor prognosis in some patients, and while these studies do not show causality, the data are compelling enough to warrant further investigation of MDR-1 reversal using new, high-activity agents. Efforts to limit this phenomenon have in the past concentrated on the use of compounds such as verapamil and ciclosporin to reverse MDR, but these drugs have little activity at doses which are not associated with toxicity.

Role Of Targeted Inhibition Now, Sandoz has presented early clinical data with its new MDR modulator, PSC 833, which suggest that targeted inhibition of PG function may have a role in the treatment of resistant tumors. PSC 833 is a ciclosporin analog which noncompetitively binds to PG and inhibits the efflux of chemotherapeutic agents. It is five- to 20-times more potent in this regard than ciclosporin, and early data suggests it may be of particular value in increasing the efficacy of the treatment of hematological tumors and certain solid tumors.