Multidrug resistance: prospects for clinical management.
Clinical success in the treatment of tumors with chemotherapy has significantly improved over the past several years. However, treatment failures due to drug resistance of cancer cells has remained a major problem. The classical form of multiple drug resistance is perhaps also the most common type of drug resistance, and represents the overexpression of a transmembrane glycoprotein pump (P-170) that mediates the efflux of a spectrum of structurally and functionally unrelated drugs. Here, we discuss recent evidence that support the concept that the total phenomenon of multiple drug resistance (MDR) involves several other mechanisms in addition to that underlying "classical" MDR. These include the action of other energy-dependent membrane efflux pumps, elevated levels of GSH for drug conjugation and detoxification to facilitate export, enhanced DNA repair facility, gene amplification and oncogene activation. The combination of mechanisms used by any particular cell line is variable and suggests that many of these mechanisms are independent. Successful reversal of drug resistance appears to require the identification of relevant operative resistance mechanisms. An example is the competitive inhibition of P-170 with verapamil, quinine and tamoxifen. A broadly successful strategy for killing drug-resistant cancer cells, however, could be based on either selective energy depletion of cancer cells or the permeabilization of tumor cells with an effective bypass of efflux pumps, since many mechanisms of drug resistance entail the energy-dependent export of toxins. The latter approach may be achieved via membrane lipid modifications or the introduction of membrane pores by biological or physical (electroporation) means.
Mansouri
A
A
Medical Research Service 151, John L. McClellan Memorial Veterans Hospital, Little Rock.
Henle
K J
KJ
Nagle
W A
WA
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D004351:Drug Resistance / Q000235:genetics; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007473:Ion Channels; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000235:genetics; D009369:Neoplasms / Q000188:drug therapy*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007473:Ion Channels; D008562:Membrane Glycoproteins; D005978:Glutathione