3 - Multidrug resistance

Summary

A major problem in cancer chemotherapy is the development of resistance by malignant cells to drugs such as vinca alkaloids or anthracyclines. Resistance may be inherent or develop after exposure to chemotherapeutic agents.

There are several mechanisms by which a cell develops resistance. My colleagues and I are concerned with a major form of multidrug resistance (MDR) that is associated with the presence of a glycoprotein of M_r 160000–180000 called P-glycoprotein (P-170) in the surface membrane of the resistant cell. In this form of drug resistance, a cell that has been exposed to a single drug expresses P-170 on its surface and simultaneously becomes resistant to a variety of other drugs of different structures that may operate by different mechanisms (Beck, 1987; Gottesman and Pastan, 1988; Endicott and Ling, 1989; van der Bliek and Borst, 1989; Burt et al., 1990; Ford and Hait, 1990).

The drugs to which the cell is resistant are usually lipophilic, with an N-containing ring and they have a slightly positive charge at physiological pH (Zamora, Pearce and Beck, 1988). Drug resistance can be at least partially reversed by less toxic agents such as verapamil (Tsuruo et al., 1981) and quinidine (Fojo et al., 1987) that inhibit the transport function of P-170. There is much evidence to show that P-170 is a relatively non-specific, energyrequiring pump with an affinity for ATP, and it is widely believed that drugs of a lipophilic nature, entering the cell, are pumped out rendering the cell resistant (Horio, Gottesman and Pastan, 1988).