Adenosine triphosphate-binding cassette proteins and bioavailability: "we can pump you up (or out)".

The adenosine triphosphate-binding cassette (ABC) superfamily of proteins (1–8) has become a prominent and important area of research in antineoplastic pharmacology and tumor cell biology (9–13). The article by Jonker et al. (14) in this issue of the Journal is an excellent example of the careful types of studies being pursued in this ever-expanding area of research. Consideration of the results of this article and others like it raises fundamental issues and questions in a variety of areas almost as disparate as the various members of the ABC superfamily and the substrates they handle. The fact that ABC proteins are inherent components of a wide range of cells and organisms should make it obvious that they were put there for a reason. Only oncologic hubris could lead one to the rather parochial opinion that these energy-dependent cellular pumps were created to produce cellular resistance to antineoplastic chemotherapy. The importance of these cellular constituents in maintenance of cellular homeostasis and tissue integrity and of protection from a wide variety of potentially damaging cellular and environmental compounds continues to be defined (1–7,15–18). This definition is occurring through ongoing identification of new members of this superfamily of proteins and demonstration of their unique, as well as overlapping, substrate specificities. One striking outcome of the large body of research in the area of ABC protein pumps is the remarkable array of reagents and resources that have been developed for use in studies in this regard. The genes responsible for most identified ABC proteins have been cloned, allowing precise genetic characterization of specific cells and cell lines and transfection and expression of specific proteins into cells that do not normally contain them. Antibodies have been raised to many of these proteins, thereby allowing histopathologic localization and immunologic quantitation of specific proteins. The availability of mdr-knockout mice represents a remarkably powerful tool for extension of these types of studies into the in vivo realm. The realization that ABC pumps handled substrates other than antineoplastic agents led to what is now a long-standing effort to modulate the pharmacology of antineoplastic agents through purposeful and specific drug–drug interactions with other classes of drugs. Initial efforts in this regard were aimed at modulating or ablating drug resistance with compounds that, through their interaction with P-glycoprotein (P-gp), would lead to increased intracellular concentrations of antineoplastic agents, such as anthracyclines, epipodophyllotoxins, and vinca alkaloids. In retrospect, the initial efforts in this regard were remarkably primitive, reflecting a less than complete understanding of what the ABC superfamily was about and a failure to understand that noncytotoxic pharmaceuticals still have limits on the plasma concentrations that can be achieved before serious adverse events appear (19,20). Despite these initial setbacks, modulating tumor resistance through pharmaceutical perturbation of ABC family members continues to represent an area of intense investigation and interest (21–25). Even with this progressively more sophisticated approach to modulating tumor-cell ABC family members, it remains to be seen whether this strategy will prove clinically relevant or feasible. One tangible result of the enormous effort to develop modulators of ABC protein pumps as a means of overcoming tumor resistance has been the identification, development, and clinical evaluation of a variety of agents known to antagonize P-gp, multidrug resistance protein, and their relatives (21–25). With the increased recognition of the range of ABC proteins has come a similar increased recognition of the various physiologic and pharmacologic roles that they play. It may be somewhat perverse that the major utility of agents designed to overcome drug resistance in tumor cells may be their ultimate application as a means to allow oral administration of antineoplastic agents, which on their own have bioavailability so limited that it has previously ruled them out as candidates for oral administration. Proof-of-principle studies in this regard have markedly changed concepts regarding the use of paclitaxel (26–28) and may ultimately change the standard of practice with that agent. The study described by Jonker et al. (14) is a logical extension of the increased knowledge regarding specific members of the ABC superfamily, the increased number of agents developed to antagonize those proteins, and an increased appreciation of the potential oral chemotherapy may play in treatment of various tumor types. Not only is oral chemotherapy more convenient for patients, it also is amenable to chronic dosing schedules, precluded by the need for intravenous administration of drugs. The results of the study by Jonker et al. (14) should also remind us of several important facts. As mentioned earlier in this editorial, ABC protein pumps have a reason for existence, and it is unlikely that conferring resistance to antineoplastic drugs is the primary reason. As clearly demonstrated, the breast cancer resistance protein (BCRP) protects fetuses from potentially damaging chemicals. Furthermore, its presence in the intestine and apically directed transport of drugs indicates that it is part of a natural and multifaceted barrier to systemic entry of potentially noxious chemicals ingested in foodstuffs. The overlapping specificity of BCRP and other ABC proteins for antitumor drugs and other pharmaceuticals should be viewed as a logical extension of their roles in that regard. With that in mind, it is incumbent on us to remember that patients are likely to ingest foods and pharmaceutical agents other than the one whose bioavailability a BCRP or P-gp modulator is intended to enhance. The potential unintended consequences of increased bioavailability of other pharmaceuticals must be carefully considered and controlled for by investigators pursuing the strategy of intentional