The role for liposomal drug delivery in molecular and pharmacological strategies to overcome multidrug resistance.

When P-glycoprotein (PGP) was first identified as a direct mediator of multidrug resistance (MDR) a great deal of excitement was generated as scientists and clinicians anticipated the ability to successfully treat previously refractory cancers by blocking this drug efflux pump. More than twenty years later there is still minimal evidence that inhibiting PGP will have widespread impact on the chemosensitivity of human tumors. Yet, we know that PGP is over-expressed in many cancers, is associated with poor prognosis in certain tumor types and, if functional, will certainly reduce the accumulation of many common anticancer drugs inside tumor cells exhibiting elevated PGP levels. Similar situations have arisen more recently for other potential mediators of chemosensitivity such as the apoptosis antagonist protein Bcl-2. Bcl-2 has been linked to drug resistance and poor patient prognosis in numerous studies. There has been a great deal of interest in blocking expression or function of this protein to increase the susceptibility of tumor cells to apoptotic stimuli such as chemotherapy. However, preclinical and clinical evidence supporting this approach as a unilateral means of significantly enhancing the response of tumors to chemotherapy is limited. In view of these examples, it would appear likely that similar caveats will be experienced in the future as new molecular targets are identified for potential MDR reversal. Given the ever increasing evidence of genetic diversity in cancer development and progression, it should not be surprising that the development of MDR is also complex and heterogeneous. Consequently, it should also not be surprising that solutions to this problem are unlikely to arise from interventions aimed at any single resistance mechanism. These concepts suggest that new approaches to addressing the various molecular and pharmacological features associated with MDR will be necessary in order to make significant in-roads into improving the clinical activity of current and future anticancer agents. This review summarizes many of the current directions being taken to overcome MDR and how liposomal drug delivery systems may play an important role in achieving this aim.