Drug and Alcohol Rehabilitation: Identification of Unique Synergistic Drug Combinations Associated With Downexpression of Survivin in a Preclinical Breast Cancer Model System.

Identification of unique synergistic drug combinations associated with downexpression of survivin in a preclinical breast cancer model system.

Filed under: Drug and Alcohol Rehabilitation

Anticancer Drugs. 2012 Mar; 23(3): 272-9
Budman DR, Calabro A, Rosen L, Lesser M

HubMed – drug

Modulation of neural activation following treatment of hepatic encephalopathy.

Filed under: Drug and Alcohol Rehabilitation

Neurology. 2013 Feb 20;
McPhail MJ, Leech R, Grover VP, Fitzpatrick JA, Dhanjal NS, Crossey MM, Pflugrad H, Saxby BK, Wesnes K, Dresner MA, Waldman AD, Thomas HC, Taylor-Robinson SD

OBJECTIVE: To measure changes in psychometric state, neural activation, brain volume (BV), and cerebral metabolite concentrations during treatment of minimal hepatic encephalopathy. METHODS: As proof of principle, 22 patients with well-compensated, biopsy-proven cirrhosis of differing etiology and previous minimal hepatic encephalopathy were treated with oral l-ornithine l-aspartate for 4 weeks. Baseline and 4-week clinical review, blood chemistry, and psychometric evaluation (Psychometric Hepatic Encephalopathy Score and Cognitive Drug Research Score) were performed. Whole-brain volumetric and functional MRI was conducted using a highly simplistic visuomotor task, together with proton magnetic resonance spectroscopy of the basal ganglia. Treatment-related changes in regional BV and neural activation change (blood oxygenation level dependent) were assessed. RESULTS: Although there was no change in clinical, biochemical state, basal ganglia magnetic resonance spectroscopy, or in regional BV, there were significant improvements in Cognitive Drug Research Score (+1.2, p = 0.003) and Psychometric Hepatic Encephalopathy Score (+1.5, p = 0.003) with treatment. This cognitive amelioration was accompanied by changes in blood oxygenation level-dependent activation in the posterior cingulate and ventral medial prefrontal cortex, 2 regions that form part of the brain’s structural and metabolic core. In addition, there was evidence of greater visual cortex activation. CONCLUSIONS: These structurally interconnected regions all showed increased function after successful encephalopathy treatment. Because no regional change in BV was observed, this implies that mechanisms unrelated to astrocyte volume regulation were involved in the significant improvement in cognitive performance.
HubMed – drug

Milatuzumab-SN-38 conjugates for the treatment of CD74+ cancers.

Filed under: Drug and Alcohol Rehabilitation

Mol Cancer Ther. 2013 Feb 20;
Govindan SV, Cardillo TM, Sharkey RM, Tat F, Gold DV, Goldenberg DM

CD74 is an attractive target for antibody-drug conjugates (ADC), because it internalizes and recycles after antibody binding. CD74 mostly is associated with hematological tumors, but is expressed also in solid cancers. Therefore, ADCs of the humanized anti-CD74 antibody, milatuzumab, were examined for the therapy CD74-expressing solid tumors. Milatuzumab-doxorubicin, and two milatuzumab-SN-38 conjugates with cleavable linkers, differing in their stability in serum and how they release SN-38 in the lysosome, were prepared. CD74 expression was determined by flow cytometry and immunohistology. In vitro cytotoxicity and in vivo therapeutic studies were performed in the human cancer cell lines A-375 (melanoma), HuH-7 and Hep-G2 (hepatoma), Capan-1 (pancreatic), NCI-N87 (gastric), and Raji Burkitt lymphoma. The milatuzumab-SN-38 ADC was compared to SN-38 ADCs prepared with anti-Trop-2 and anti-CEACAM6 antibodies in xenografts expressing their target antigens. Milatuzumab-doxorubicin was most effective in the lymphoma model, while in A-375 and Capan-1 solid tumors, only milatuzumab-SN-38 showed a therapeutic benefit. Despite much lower surface expression of CD74 than Trop-2 or CEACAM6, milatuzumab-SN-38 had similar efficacy in Capan-1 as anti-Trop-2-SN-38, but in NCI-N87, anti-CEACAM6 and anti-Trop-2 conjugates were superior. Studies in 2 hepatoma lines at a single dose level showed significant benefit over saline controls, but not against an irrelevant IgG conjugate. CD74 is a suitable target for ADCs in some solid tumor xenografts, with efficacy largely influenced by uniformity of CD74 expression, and with SN-38 conjugates providing the best therapeutic responses; SN-38 conjugates were preferable in solid cancers, while doxorubicin ADC was better in lymphoma tested.
HubMed – drug

Regulation of mRNA Export by the PI3 kinase / AKT Signal Transduction Pathway.

Filed under: Drug and Alcohol Rehabilitation

Mol Biol Cell. 2013 Feb 20;
Quaresma AJ, Sievert R, Nickerson JA

UAP56, ALY/REF, and NXF1 are mRNA export factors that sequentially bind at the 5′ end of a nuclear mRNA, but are also reported to associate with the Exon Junction Complex (EJC). To screen for signal transduction pathways regulating mRNA export complex assembly we used Fluorescence Recovery after Photobleaching (FRAP) to measure the binding of mRNA export and EJC core proteins in nuclear complexes. The fraction of UAP56, ALY/REF, and NXF1 tightly bound in complexes was reduced by drug inhibition of the PI3 kinase / AKT pathway, as was the tightly bound fraction of the core EJC proteins eIF4A3, MAGOH, and Y14. Inhibition of the mTOR mTORC1 pathway decreased the tight binding of MAGOH. Inhibition of the PI3 Kinase/AKT pathway increased the export of poly(A) RNA and of a subset of candidate mRNAs. A similar effect of PI3 kinase/AKT inhibition was observed for mRNAs from both intron-containing and intron-less Histone genes. However, the nuclear export of mRNAs coding for proteins targeted to the Endoplasmic Reticulum or to Mitochondria was not affected by the PI3 kinase/AKT pathway. These results show that the active PI3 kinase/AKT pathway can regulate mRNA export and can promote the nuclear retention of some mRNAs.
HubMed – drug

More Drug And Alcohol Rehabilitation Information…