Membrane transport alterations as a mechanism of resistance to anticancer agents.

An alteration in membrane transport is one of the most common mechanisms by which tumour cells become resistant to anticancer agents and represents one of the major obstacles in present cancer chemotherapy. A recent emphasis on understanding the mechanisms by which drugs are transported into cells should continue to assist attempts to overcome these problems. Resistance in certain instances can be overcome by modifications in the structure of a drug which increases lipophilicity. These successes have usually been obtained where well defined transport processes are present and specific deletions or modifications in the putative transport proteins are apparent, as in the case of classical antifolates. Simplicity, however, never seems to prevail and recent evidence indicates that cells can prevent transport of lipophilic drugs perhaps by modification of the chemical structure or properties of the plasma membrane, as in the case of trimetrexate. Some alkylating agents are transported by well defined carrier systems; for example, nitrogen mustard enters cells by the choline carrier, and melphalan uses two distinct amino acid carrier mechanisms. For both of these agents, tumour cell resistance is sometimes caused by transport defects. Resistance to antitumour nucleosides may be associated with impaired transport, and this has been demonstrated most clearly for cytarabine and fluorodeoxyuridine. In the case of antitumour antibiotics, although resistance is most often associated with a pleiotropic resistance phenotype in which the rate of drug efflux from the cell is increased, certain cases will be discussed in which resistance may be clearly attributed to defective drug uptake.