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

Many attempts to circumvent P-glycoprotein (PGP)based multidrug resistance (MDR) in cancer chemotherapy have utilized PGP blocking agents (also referr ed to as MDR modulators), which are co-administered with the anticancer dru g. This approach is based on the premise that inhibiting PGP function will result ill increased accumulation of many anticancer drugs in the tumor cel ls and restore full antitumor activity. However, co-administration of MDR m odulators 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 f unctions in healthy tissues, such as liver and kidney, which markedly I edu ces anticancer drug clearance properties. Two consequences of these pharmac okinetic interactions are: 1. Increased toxicity due to modulator-induced c hanges in biodistribution proper-ties of the anticancer drug. 2. Problems i nterpreting preclinical and clinical data with respect to: a) Are therapeut ic improvements due to altered pharmacokinetics or PGP modulation within th e tumor cells? And, b) Does decreasing the anticancer drug dose to that whi ch is equitoxic in the absence of the modulator potentially compromlse tumo r therapy clue to decreased anticancer drug levels in the tumor tissue? Alt hough many of the difficulties associated with co-administration of MDR mod ulators and anticancer drugs are manifested by toxicity effects, it is ulti mately the ability to obtain effective antitumor activity against resistant tumors that will determine the utility of chemosensitization approaches. L iposomes appear to be weil 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 primar ily responsible for the attenuated therapy of extravascular MDR solid tumor s overexpressing PGP. Liposomal carriers have been utilized to provide tumo r selective delivery of anticancer agents as well as to circumvent many tox icities associated with these agents by altering the pharmacodistribution p roperties of encapsulated drugs (1-4). Given the pharmacokinetic changes in duced by the MDR modulators on non-encapsulated doxorubicin (DOX), we propo sed that liposomes may limit these effects by virtue of their ability to re duce 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 the se toxicity buffering effects, the effect of PGP blockade on the cellular u ptake of DOX in the tumor may be able to be selectively increased using lip osomal carriers. This is based on the ability of small liposomes to passive ly extravasate in tumors (1,2,8,9) as well as their inability to accumulate in healthy susceptible tissues. By studying the toxicity and efficacy prop erties Of liposome encapsulated DOX in combination with the MDR modulator P SC 833 we have been able to demonstrate that two factors play a major role in determining the effectiveness of chemosensitization approaches to overco me MDR; 1) optimizing selective localization of anticancer drug localizatio n in tumor tissue and 2) effective blockade of PGP in tumor cells under con ditions 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.