Multidrug resistance represents a major obstacle in the successful the
rapy of neoplastic diseases. Studies have demonstrated that this form
of drug resistance occurs both in cultured tumor cell lines as well as
in human cancers. P-glycoprotein appears to play an important role in
such cells by acting as an energy-dependent efflux pump to remove var
ious natural product drugs from the cell before they have a chance to
exert their cytotoxic effects. Expression of the MDR1 gene product has
been associated with a poor prognosis in clinical studies. It has bee
n demonstrated in the laboratory that resistance mediated by the P-gly
coprotein may be modulated by a wide variety of compounds. These compo
unds, which include verapamil and cyclosporin, generally have little o
r no effect by themselves on the tumor cells, but when used in conjunc
tion with antineoplastic agents, they decrease, and in some instances
eliminate, drug resistance. Clinical trials to modulate P-glycoprotein
activity are underway at the present time to determine if such strate
gies will be feasible. Although the P-glycoprotein is expressed in man
y cell lines and occurs in patient tumors, its expression is not a uni
versal feature of multidrug resistance, suggesting that other mechanis
ms are operating.