Stephanie van Hoppe

16 Chapter 1 been as yet elusive, not only for cancer therapy, but also for other drugs targeting CNS diseases (23-25). It is fair to say that we don’t think there is a longer-term future for chronic clinical administration of strong ABCB1 and ABCG2 inhibitors together with targeted anticancer drugs, especially when it concerns improving brain (tumor) access. It is risky to completely inhibit ABCB1 and ABCG2 in the blood-brain barrier of patients in a chronic setting, as would be required for clinical treatment withmost targeted anticancer drugs. Unpredictable (CNS) toxicity of drugs, pesticides and even some food components, to which suchpatientswill inevitably be exposed, might emerge. Indeed, we have observed severe and sometimes lethal toxicity of otherwise well tolerated drugs, pesticides, and even food components in ABCB1 and/or ABCG2 knockout mouse strains due to highly increased availability of these compounds (26-28). In our view, the future lies in the development of effective targeted anticancer drugs that are no longer transported substrates of ABCB1 and ABCG2. This appears to be difficult to achieve, likely related to the many other constraints of developing efficacious new drugs: we estimate that at least 90% of targeted anticancer drugs that have been registered over the past 10 years are significantly transported by either or both of these ABC transporters. However, it does appear to be feasible if a dedicated effort is made [e.g.,(29)]. Such “untransported” drugs would combine the advantages of being no longer susceptible to multidrug resistance mediated by ABCB1 and ABCG2 present in tumor cells, and of having relatively enhanced access to brain (tumor) tissue. Obtaining such compounds should therefore be a main goal for pharmaceutical companies developing new anticancer drugs, especially those targeting tumors or metastases positioned in whole or in part behind the blood-brain barrier.