Strategies to circumvent multidrug resistance due to P-glycoprotein or to altered DNA topoisomerase II

Abstract

Strategies to circumvent different forms of multidrug resistance (MDR) in tumor cells will be discussed. The form of MDR associated with overexpression of P-glycoprotein. Pgp-MDR, is well-understood, and its features are briefly described. Many clinically useful lipophilic organic bases have been shown to interfere with drug efflux mediated by Pgp, consequently circumventing or overcoming this form of MDR. Based on these empiric observations, screening and molecular modeling efforts are being employed to develop new modulators of Pgp-MDR. However, because inhibition of normal tissue Pgp can cause unacceptable toxicities, new strategies to circumvent Pgp-MDR in tumors must be sought. Possibilities range from pharmacokinetic modeling to the development of tissue-specific inhibitory antibodies or antisense oligonucleotides. Tumor cells expressing altered DNA topoisomerase II express a more restricted form of MDR, termed at-MDR, that will be discussed briefly and compared with Pgp-MDR. Modulators of Pgp-MDR are without effect in cells expressing only at-MDR. However, some analogs of anthracyclines appear to act via a topo II-independent pathway and can circumvent this form of resistance. Also, alterations in topoisomerase II may have consequences for other cellular functions, as at-MDR cells appear to have defects in DNA repair pathways, suggesting other areas for therapeutic exploitation.