The use of liposomal anticancer agents to determine the roles of drug pharmacodistribution and P-glycoprotein (PGP) blockade in overcoming multidrug resistance (MDR). (2000)

Many attempts to circumvent P-glycoprotein (PGP)-based multidrug resistance (MDR) in cancer chemotherapy have utilized PGP blocking agents (also referred to as MDR modulators), which are co-administered with the anticancer drug. This approach is based on the premise that inhibiting PGP function will result in increased accumulation of many anticancer drugs in the tumor cells and restore full antitumor activity. However, co-administration of MDR modulators with anticancer drugs has often resulted in exacerbated toxicity of the anticancer drugs and limited chemosensitization of MDR tumors. These problems appear to be related to MDR modulator blockade of PGP excretory functions in healthy tissues, such as liver and kidney, which markedly reduces anticancer drug clearance properties. Two consequences of these pharmacokinetic interactions are: 1. Increased toxicity due to modulator-induced changes in biodistribution properties of the anticancer drug. 2. Problems interpreting preclinical and clinical data with respect to: a) Are therapeutic improvements due to altered pharmacokinetics or PGP modulation within the tumor cells? And, b) Does decreasing the anticancer drug dose to that which is equitoxic in the absence of the modulator potentially compromise tumor therapy due to decreased anticancer drug levels in the tumor tissue? Although many of the difficulties associated with co-administration of MDR modulators and anticancer drugs are manifested by toxicity effects, it is ultimately the ability to obtain effective antitumor activity against resistant tumors that will determine the utility of chemosensitization approaches. Liposomes appear to be well suited to solve many of the problems noted above that are associated with conventional anticancer drugs and MDR modulators. In view of these considerations, we have hypothesized that inadequate tumor delivery of anticancer agents and selectivity of PGP modulation are primarily responsible for the attenuated therapy of extravascular MDR solid tumors overexpressing PGP. Liposomal carriers have been utilized to provide tumor selective delivery of anticancer agents as well as to circumvent many toxicities associated with these agents by altering the pharmacodistribution properties of encapsulated drugs (1-4). Given the pharmacokinetic changes induced by the MDR modulators on non-encapsulated doxorubicin (DOX), we proposed that liposomes may limit these effects by virtue of their ability to reduce the exposure of encapsulated DOX to the kidneys and alter clearance of DOX in the liver (5,6). These tissues appear to be key factors involved in modulator-induced DOX pharmacokinetic changes (7). In conjunction with these toxicity buffering effects, the effect of PGP blockade on the cellular uptake of DOX in the tumor may be able to be selectively increased using liposomal carriers. This is based on the ability of small liposomes to passively extravasate in tumors (1,2,8,9) as well as their inability to accumulate in healthy susceptible tissues. By studying the toxicity and efficacy properties of liposome encapsulated DOX in combination with the MDR modulator PSC 833 we have been able to demonstrate that two factors play a major role in determining the effectiveness of chemosensitization approaches to overcome MDR; 1) optimizing selective localization of anticancer drug localization in tumor tissue and 2) effective blockade of PGP in tumor cells under conditions that do not compromise anticancer drug accumulation into the tumor. Failure to achieve both of these conditions simultaneously may be expected to result in substantially reduced therapy of MDR tumors.