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101.
102.
This study aimed to express two major drug-metabolizing human hepatic cytochromes P450 (CYPs), CYP2D6 and CYP3A4, together
with NADPH-cytochrome P450 oxidoreductase (OxR) in Escherichia coli and to evaluate their catalytic activities. Full length cDNA clones of both isoforms in which the N-terminus was modified
to incorporate bovine CYP17α sequence were inserted into a pCWori+ vector. The modified CYP cDNAs were subsequently expressed individually, each together with OxR by means of separate, compatible
plasmids with different antibiotic selection markers. The expressed proteins were evaluated by immunoblotting and reduced
CO difference spectral scanning. Enzyme activities were examined using high performance liquid chromatography (HPLC) assays
with probe substrates dextromethorphan and testosterone for CYP2D6 and CYP3A4, respectively. Results from immunoblotting demonstrated
the presence of both CYP proteins in bacterial membranes and reduced CO difference spectra of the cell preparations exhibited
the characteristic absorbance peak at 450 nm. Co-expressed OxR also demonstrated an activity level comparable to literature
values. Kinetic parameters, Km and Vmax values determined from the HPLC assays also agreed well with literature values. As a conclusion, the procedures described
in this study provide a relatively convenient and reliable means of producing catalytically active CYP isoforms suitable for
drug metabolism and interaction studies. 相似文献
103.
Carter BZ Mak DH Morris SJ Borthakur G Estey E Byrd AL Konopleva M Kantarjian H Andreeff M 《Apoptosis : an international journal on programmed cell death》2011,16(1):67-74
XIAP, a potent caspase inhibitor, is highly expressed in acute myeloid leukemia (AML) cells and contributes to chemoresistance.
A multi-center phase 1/2 trial of XIAP antisense oligonucleotide AEG35156 in combination with idarubicin/cytarabine was conducted
in 56 patients with relapsed/refractory AML. Herein we report the pharmacodynamic studies of the patients enrolled at M. D.
Anderson Cancer Center. A total of 13 patients were enrolled in our institution: five in phase 1 (12–350 mg/m2 AEG35156) and eight in phase 2 (350 mg/m2 AEG35156) of the protocol. AEG35156 was administered on 3 consecutive days and then weekly up to a maximum of 35 days. Blood
samples were collected from patients on days 1 through 5 and on day 28–35 post-chemotherapy for detection of XIAP levels and
apoptosis. AEG35156 treatment led to dose-dependent decreases of XIAP mRNA levels (42–100% reduction in phase 2 patients).
XIAP protein levels were reduced in all five samples measured. Apoptosis induction was detected in 1/4 phase 1 and 4/5 phase
2 patients. Importantly, apoptosis was most pronounced in CD34
+
38
−
AML stem cells and all phase 2 patients showing apoptosis induction in CD34
+
38
−
cells achieved response. We conclude that at 350 mg/m2, AEG35156 is effective in knocking down XIAP in circulating blasts accompanied by the preferential induction of apoptosis
in CD34
+
38
−
AML stem cells. 相似文献
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Vivet-Boudou V Isel C Sleiman M Smyth R Ben Gaied N Barhoum P Laumond G Bec G Götte M Mak J Aubertin AM Burger A Marquet R 《PloS one》2011,6(11):e27456
The occurrence of resistant viruses to any of the anti-HIV-1 compounds used in the current therapies against AIDS underlies the urge for the development of new drug targets and/or new drugs acting through novel mechanisms. While all anti-HIV-1 nucleoside analogues in clinical use and in clinical trials rely on ribose modifications for activity, we designed nucleosides with a natural deoxyribose moiety and modifications of position 8 of the adenine base. Such modifications might induce a steric clash with helix αH in the thumb domain of the p66 subunit of HIV-1 RT at a distance from the catalytic site, causing delayed chain termination. Eleven new 2'-deoxyadenosine analogues modified on position 8 of the purine base were synthesized and tested in vitro and in cell-based assays. In this paper we demonstrate for the first time that chemical modifications on position 8 of 2'-deoxyadenosine induce delayed chain termination in vitro, and also inhibit DNA synthesis when incorporated in a DNA template strand. Furthermore, one of them had moderate anti-HIV-1 activity in cell-culture. Our results constitute a proof of concept indicating that modification on the base moiety of nucleosides can induce delayed polymerization arrest and inhibit HIV-1 replication. 相似文献
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In our work evaluating the antioxidant properties of a number of cardiovascular drugs, we have emphasized the importance of lipophilicity as a property contributing to antioxidant potency. Thus, the dihydropyridine calcium channel blockers and propranolol, one of the most lipophilic beta-blockers, were found to exhibit the greatest potency in membrane and cellular models. Both beta-blockers and calcium channel blockers are classified as antihypertensive agents. We found that the specific chemical moieties of various drugs may participate in the antioxidant mechanism of action. While reviewing relevant work from the past literature, it became apparent that some of the chemical moieties of antihypertensive and vasodilator drugs may bind transition metals. Thus, this present review focuses on common properties of transition metal-interaction that are shared, to a greater or lesser degree, by a number of vasoactive drugs and chemical agents. Although this observation has been pursued by other investigators in the past, we submit that the potential relevance to the newer pharmacological agents needs to be explored further. In addition, new information regarding the role of transition metals and free radicals involving vascular cells focuses greater importance on transition metal-interaction as a potential mechanism in vasodilation. This review does not intend to be inclusive of all chemical structures capable of binding transition metals; only those that are clinically relevant will be considered in some detail. Potential mechanisms of metal-chelating actions leading to vasodilation are also discussed. 相似文献