The development of multidrug resistance (MDR) in patients suffering cancer remains a significant clinical challenge, with drug efflux by ABC (ATP-binding cassette) transporters contributing significantly. Theoretically, one could restore the efficacy of first-line drugs by circumventing these resistance mechanisms. However, cancer is a heterogeneous disease that can exhibit different characteristics from patient to patient or even within a single patient. Spatial and temporal heterogeneity is a result of continuous adaptation to selective pressures through sequential genetic changes that ultimately convert a normal cell into intractable cancer. Thus, cancer cells are moving targets, as individual cells in a tumor mass constantly adapt to local environmental challenges. Biological membranes represent a significant permeation barrier and thus play a critical role in the protection of pharmacokinetic compartments. Conversely, the activity of a drug ultimately depends on the ability of the compound to reach its target, which might reside in a well-protected pharmacological sanctuary.
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