Pharmacological considerations in the modulation of multidrug resistance

Abstract

INTRODUCTION MULTIDRUG RESISTANCE (MDR) is the phenomenoninwhich cancer cells become resistant to an array of chemotherapeutic agents with dissimilar structures and mechanisms of action [ 11. MDR can be mediated by the overexpression of a multidrug transporter, the best studied of which is termed Pglycoprotein (Pgp) [2-61. Pgp is a 170 kd plasma membrane protein with twelve transmembrane domains and two intracellular ATPase sites [7]. Pgp has broad specificity as an energy-dependent efflux pump and effectively transports a variety of amphipathic compounds out of the cell. Substrates for Pgp include many anticancer drugs, most notably those derived from natural products (Table 1). Many intrinsically chemoresistant cancers overexpress Pgp de nova. Other classically chemosensitive malignancies such as breast, ovarian and haematolymphoid cancers seldom express Pgp at diagnosis, yet have a high proportion of cases overexpressing Pgp upon relapse. Several studies have found Pgp expression to be predictive of poor response to chemotherapy and decreased overall survival (see reviews [8-l 01). Expression of Pgp also occurs in certain normal tissues (Table 2). Its presence on the apical surface of cells lining the lumen of large and small bowel, bile canaliculi and proximal renal tubules suggests that it may play a role in the excretion of potentially toxic xenobiotics [l 11. Furthermore, the Pgp expressed along the intraluminal surface of vascular endothelium comprising the blood-brain barrier, placenta and blood-testes barrier may play a role in protecting the CNS (central nervous system), fetus and germinal cells from toxic substances in the circulation [12, 131. Its function in other normal tissues remains a matter of conjecture. The calcium channel blocker, verapamil, was the first noncytotoxic agent found to inhibit the Pgp efflux pump in vitro [ 141. Soon thereafter, numerous other currently approved medications were shown to be modulators of drug resistance in vitro (see Table 3). The potential clinical benefit to be derived from a potent Pgp inhibitor has spawned a new field of drug development and clinical research on the modulation of multidrug resistance (MDR). The purpose of this paper is to review the clinical pharmacology of selected Pgp inhibitors and to assess the impact of normal tissue Pgp inhibition on the disposition and elimination of chemotherapeutic agents.