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Background and Purpose: ABC multidrug transporters (MDR-ABC proteins) cause multiple drug resistance in cancer and may be involved in the decreased anti-cancer efficiency and modified pharmacological properties of novel specifically targeted agents. It has been documented that ABCB1 and ABCG2 interact with several first-generation, small-molecule, tyrosine kinase inhibitors (TKIs), including the Bcr-Abl fusion kinase inhibitor imatinib, used for the treatment of chronic myeloid leukaemia. Here, we have investigated the specific interaction of these transporters with nilotinib, dasatinib and bosutinib, three clinically used, second-generation inhibitors of the Bcr-Abl tyrosine kinase activity.Experimental Approach: MDR-ABC transporter function was screened in both membrane- and cell-based (K562 cells) systems. Cytotoxicity measurements in Bcr-Abl-positive model cells were coupled with direct determination of intracellular TKI concentrations by high-pressure liquid chromatography-mass spectrometry and analysis of the pattern of Bcr-Abl phosphorylation. Transporter function in membranes was assessed by ATPase activity.Key Results: Nilotinib and dasatinib were high-affinity substrates of ABCG2, and this protein mediated an effective resistance in cancer cells against these compounds. Nilotinib and dasatinib also interacted with ABCB1, but this transporter provided resistance only against dasatinib. Neither ABCB1 nor ABCG2 induced resistance to bosutinib. At relatively higher concentrations, however, each TKI inhibited both transporters.Conclusions and Implications: A combination of in vitro assays may provide valuable preclinical information for the applicability of novel targeted anti-cancer TKIs, even in multidrug-resistant cancer. The pattern of MDR-ABC transporter-TKI interactions may also help to understand the general pharmacokinetics and toxicities of new TKIs. [ABSTRACT FROM AUTHOR]

Objectives: To compare the neonatal and maternal morbidity data associated with induced or naturally conceived pregnancies of primiparous women aged 35 years and older. Methods: We recruited primiparous women aged 35 years and older, who delivered between January 1995 and December 2000. The outcomes of the induced (n=62) and naturally conceived (n=132) pregnancies were compared. The Fisher exact test was used for univariate analysis in order to compare the delivery and pregnancy characteristics in the two groups. Results: Cesarean section featured with a 0.76 times lower prevalence among the induced pregnant women, than among the spontaneous ones, but the difference was not significant statistically. The induced pregnancies were not associated with a significantly higher rate of perinatal complications. Conclusions: Induced pregnancy does not involve a higher risk of maternal complications. The incidence of premature newborns and intrauterine growth retardation was high in both subgroups, but without a statistically significant difference. [Copyright &y& Elsevier]