A number of cytostatic compounds (2-4, 7, and 8), which can be described as "diaryl", inhibit tubulin polymerization, cause cells to accumulate in mitotic arrest, and competitively inhibit the binding of colchicine to tubulin. They differ, however, in the separation of the two aryl moieties. To attempt to understand this variability we prepared a series of analogues modeled on 3 and 4 ("benzodioxole series") and on 7 and 8 ("combretastatin series") which differed only in the number of methylene units (ranging from none to four) separating the aryl moieties. These compounds were evaluated for their effects on tubulin polymerization, colchicine binding, and the growth of L1210 murine leukemia cells. In terms of inhibitory effects on tubulin polymerization, for the combretastatin series there was an optimal separation of the two phenyl rings by a two-carbon bridge (compound 24), with progressively decreasing inhibitory activity when the separation was by one carbon (20), three carbons (25), or four carbons (28) (the biphenyl analogue 16 was inactive). The benzodioxole series, however, did not permit us to generalize this finding, because the least active agents prepared (39 and 40) had a two-carbon bridge, while those with one- (5 and 6) and three-carbon (46 and 47) bridges were nearly equivalent in potency. Submicromolar IC50 values for inhibition of L1210 cell growth were only obtained for compounds 20 (IC50, 0.2 microM), 24 (0.07 microM), and 25 (0.4 microM). While evaluating the effects of these agents on tubulin polymerization, we noted with the combretastatin series and with several standard agents that apparent potency (in terms of IC50 values) was always lower if the reaction was performed at 30 degrees C, with 0.25 mM MgCl2, than at 37 degrees C, with 1.0 mM MgCl2. This enhancement of IC50 values in the former system as compared with the latter was particularly dramatic for the less active agents (e.g., 28) as compared with the more active (e.g. 24).
BackgroundAlzheimer's disease (AD) is the most common cause of dementia, accounting for an estimated 60 to 80% of cases, and is the sixth-leading cause of death in the United States. While considerable advancements have been made in the clinical care of AD, it remains a complicated disorder that can be di cult to identify de nitively in its earliest stages. Recently, mass spectrometry (MS)-based metabolomics has shown signi cant potential for elucidation of disease mechanisms and identi cation of therapeutic targets as well diagnostic and prognostic markers that may be useful in resolving some of the di culties affecting clinical AD studies, such as effective strati cation. MethodsIn this study, complementary gas chromatography-and liquid chromatography-MS platforms were used to detect and monitor 2,080 metabolites and features in 48 post-mortem tissue samples harvested from the superior frontal gyrus of male and female subjects. Samples were taken from four groups: 12 normal control (NC) patients, 12 cognitively normal subjects characterized as high pathology controls (HPC), 12 subjects with non-speci c mild cognitive impairment (MCI), and 12 subjects with AD. ResultsMultivariate statistics informed the construction and cross-validation (p < 0.01) of partial least squaresdiscriminant analysis (PLS-DA) models de ned by a 9-metabolite panel of disease markers (lauric acid, stearic acid, myristic acid, palmitic acid, palmitoleic acid, and four unidenti ed mass spectral features). Receiver operating characteristic analysis showed high predictive accuracy of the resulting PLS-DA models for discrimination of NC (97%), HPC (92%), MCI (~ 96%), and AD (~ 96%) groups. Pathway analysis revealed signi cant disturbances in lysine degradation, fatty acid metabolism, and the degradation of branched-chain amino acids. Network analysis showed signi cant enrichment of 11 enzymes, predominantly within the mitochondria. ConclusionsThe results expand basic knowledge of the metabolome related to AD and reveal pathways that can be targeted therapeutically. This study also provides a promising basis for the development of larger multisite projects to validate these candidate markers in readily available biospecimens such as blood to enable the effective screening, rapid diagnosis, accurate surveillance, and therapeutic monitoring of AD. BackgroundImportantly, this study provides clinically relevant candidate biomarkers capable of accurate post-mortem classi cation which may, eventually, prove useful to in vivo diagnosis and disease monitoring. Methods ReagentsAcetonitrile (ACN), methanol (MeOH), ammonium acetate (NH 4 OAc), acetic acid (AcOH), and isopropanol (IPA), all LC-MS grade, were purchased from Fisher Scienti c (Pittsburgh, PA). Ammonium hydroxide (NH 4 OH), methyl tert-butyl ether (MTBE), O-methylhydroxylamine hydrochloride (MeOX), and N-Methyl-N-(tert-butyldimethylsilyl) tri uoroacetamide (MTBSTFA) were bought from Sigma-Aldrich (Saint Louis, MO). High performance LC grade chloroform (CHCl 3 ) was obtained from VWR (Radnor, P...
Twenty-six patients with metastatic breast cancer who had previously responded to one or more endocrine therapies participated in a clinical trial of the combination of trilostane and hydrocortisone for subsequent disease progression. Of these, one patient achieved complete remission (4%), and five had partial response (19%). The median time to progression from initiation of therapy for responding patients was six months (range: 4 - 32 + months). Major toxicities included nausea/vomiting (16 patients), facial flushing (14), abdominal cramping (11), and oral paresthesia (10). Therapy was discontinued in four patients (15%) because of drug intolerance. Fourteen patients who failed trilostane were treated with aminoglutethimide and hydrocortisone. Six patients showed objective response (PR + MR). These data show that trilostane and hydrocortisone in combination can produce an objective response in a significant fraction of patients and that the combination has a different spectrum of toxicity from aminoglutethimide/hydrocortisone. A small number of patients crossed over to aminoglutethimide showed a few objective responses, suggesting a partial lack of cross-resistance between the two antiadrenal drugs.
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