Multidrug resistance and cancer: the role of the human ABC transporter ABCG2

A variety of human cancers become resistant or are intrinsically resistant to treatment with conventional chemotherapy, a phenomenon called multidrug resistance. This broad-based resistance results in large part, but not solely, from overexpression of members of the ATP-binding cassette (ABC) superfamily of membrane transporters, including P-glycoprotein, various members of the multidrug resistance associated proteins (MRPs), and ABCG2, also known as MXR1, BCRP, and ABCP. When overexpressed in cell lines, ABCG2 has the ability to confer high levels of resistance to anthracyclines, mitoxantrone, bisantrene, and the camptothecins topotecan and SN-38. This review focuses on the discovery, the biochemistry and the normal physiology of human ABCG2, a novel ABC half transporter expressed abundantly in placenta, as well as in liver, intestine and stem cells. ABCG2 may serve a protective function by preventing toxins from entering cells as well as potentially playing a role in regulating stem cell differentiation. We also discuss the involvement of ABCG2 in multidrug resistance in cancer, especially with regard to acute myeloid leukemia. The mechanism by which substrates are recognized by ABCG2 and how the energy of ATP hydrolysis is transduced into transport remain elusive. A complete understanding of the mechanism and biological function of ABCG2 will be important for understanding its normal physiology as well as potentially for the development of novel chemotherapeutic treatment strategies.     

Tests for specific nonparametric relations between two distribution functions with applications

Let (X,Y) be a random vector and let G and H be the marginal distributions of X and Y, respectively. In this paper, we propose two tests, one of Kolmogorov‐Smirnov type and the other of Wilcoxon type, for the null hypothesis Ψ(G) = H against the alternative Ψ(G) < H, where Ψ() is a function such that Ψ(G) is a distribution function. The tests are based on the empirical distribution functions of the observations on X and Y, which are dependent. We obtain their asymptotic null distributions. A suspected relationship between the distribution functions of two dependent outcomes can be specified as a hypothesis to be tested in examples like the load sharing models, record values, and auction bidding models. As an application, we consider in detail the problem of testing the effect of load sharing in two component parallel systems.