Ternary combination of irinotecan, fluorouracil-folinic acid and oxaliplatin: results on human colon cancer cell lines

A marked antitumour efficacy is currently obtained by oxaliplatin (LOHP)–fluorouracil (FU)–folinic acid (FA) combination and by CPT11–FU–FA combination. Logically, the triple association LOHP, CPT11 and FUFA will be soon tested in cancer patients. The aim of the present study was to compare two schedules combining SN38 (the active metabolite of CPT11, irinotecan) with FU–FA and LOHP. The two schedules differed by the SN38 position. The relative contribution of each drug in the resulting global cytotoxicity was evaluated. Two human colon cancer cell lines were used (WIDR and SW620 both p53 mutated). LOHP plus FA were applied for 2 h, just before a 48 h FU exposure. The SN38 sequence was applied for 24 h, starting either 48 h before LOHP-FA (schedule A), or just after LOHP-FA exposure (schedule B). Cytotoxicity was assessed by the 3-(4,5-demethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) test and drug interactions were analysed according to the Chou and Talalay method, based on the computation of a combination index (CI). The SN38 position significantly induces a shift from additivity-antagonism when SN38 was applied after LOHP, towards additivity-synergism when SN38 was applied first (P = 0.03). The relative contribution (RC) of each drug in the overall cytotoxicity of the triple combination was defined as the drug concentration giving 50% cell lethality (IC 50) of the double association without that drug divided by the IC 50 of the triple association. Whatever the SN38 position, the larger contribution was made by LOHP (median RC = 2.4) and the smaller by SN38 (median RC = 1.1). In addition, the contribution of FUFA was improved when SN38 was applied first (median RC = 2.2) as compared to the opposite schedule (median RC = 1.2). Results were in agreement between the two explored cell lines. The present data should be taken into account when establishing the rationale of future trials combining CPT11, LOHP and FU–FA. © 2001 Cancer Research Campaign http://www.bjcancer.co

Impact of thymidine phosphorylase surexpression on fluoropyrimidine activity and on tumour angiogenesis

Tumoral thymidine phosphorylase (TP) appears to play a dual role by being involved in neoangiogenesis and by activating 5FU prodrugs at the tumoral target site. The aim of the study was to investigate more thoroughly these potential physiological and pharmacological roles of TP. A rat carcinoma cell line (PROb) was transfected with TP/PD-ECGF in order to study the effect of the overexpression of this enzyme (1) on the sensitivity of cells to 5′DFUR and 5FU in vitro and (2) on tumour growth in vivo by using a syngenic tumour model in the BDIX rat (hepatic tumours, sub-cutaneous tumours). Cytotoxic effects of 5′DFUR, and to a lesser extent those of 5FU, were enhanced in TP clones as compared to control cells: there was a highly significant correlation between TP activity and in vitro sensitivity to 5’DFUR (r2= 0.91, P = 0.0002, n = 8) and, to a lesser extent, to 5FU (r2= 0.49, P = 0.053, n = 8). The impact of TP transfection on tumour growth was relatively modest and concerned only the initial stages of tumour expansion. Staining of TP tumours for endothelial (factor VIII) cells was always higher than controls. The staining ratio (TP/controls) tended to be reduced as tumours increased in size. The stability of TP expression was checked both in vitro (TP activity measurement) and in vivo (RT-PCR determinations) and there was no loss of TP expression over time which could be advanced to explain the progressive weakening of the impact of TP overexpression on both tumour growth and neoangiogenesis. © 2001 Cancer Research Campaign http://www.bjcancer.co

Benthic foraminiferal assemblages and test accumulation in coastal microhabitats on San Salvador, Bahamas

Benthic foraminiferal populations were studied in a shallow bay of San Salvador Island, the Bahamas. Surface sediments and marine macrophytes were collected from 14 sample sites along a 500&thinsp;m transect at Grahams Harbour to investigate the foraminiferal assemblage in each microhabitat and to test the link between dead foraminiferal test accumulation patterns and living epiphytic and sedimentary foraminiferal assemblages, macrophyte distribution, and environmental gradients. The analyses include grain size measurements, macrophyte biomass quantification, and qualitative and quantitative studies of benthic foraminifera. The foraminifera found attached to macrophytes differed between macrophyte habitats. However, a correlation between these living communities and the dead assemblages in the sediments at the same sites could not be observed. Principal component analysis (PCA) and redundancy analysis (RDA) suggest that the presence of the macroalgae Halimeda explains 16&thinsp;% of the residual faunal variation in the dead foraminiferal assemblage after the effects of sorting according to fall speed are partialled out. The RDA also reflects a positive correlation between foraminifera larger than 1.0&thinsp;mm in diameter and the 0.25–0.5&thinsp;mm sediment grain size, indicating sedimentological processes as the main factor controlling the sedimentary epiphytic foraminiferal assemblages. These sedimentary processes overprint most effects of ecological features or macrophyte-specific association.</p

Wind Circulation in Selected Rotating Magnetic Early-B Stars

The rotating magnetic B stars have oblique dipolar magnetic fields and often anomalous helium and metallic compositions. These stars develop co-rotating torus-shaped clouds by channelling winds from their magnetic poles to an anchored planar disk over the magnetic equator. The line absorptions from the cloud can be studied as the complex rotates and periodically occults the star. We describe an analysis of the clouds of four stars (HD184927, beta Cep, sigma Ori E, and HR6684). From line synthesis models, we find that the metallic compositions are spatially uniform over the stars' surfaces. Next, using the Hubeny CIRCUS code, we demonstate that periodic UV continuum fluxes can be explained by the absorption of low-excitation lines. The analysis also quantifies the cloud temperatures, densities, and turbulences, which appear to increase inward toward the stars. The temperatures range from about 12,000K for the weak Fe lines up to temperatures of 33,000K for N V absorptions, which is in excess of temperatures expected from radiative equilibrium. The spectroscopic hallmark of this stellar class is the presence of strong C IV and N V resonance line absorptions at occultation phases and of redshifted emissions at magnetic pole-on phases. The emissions have characteristics which seem most compatible with the generation of high-energy shocks at the wind-cloud interface, as predicted by Babel.Comment: 19 pages, Latex plus 6 figures A&A single-spaced, accepted by Astronomy & Astrophysics. Files available by ftp at nobel.stsci.edu/pub/aapaper

Resolution of Biphasic Binding of the Opioid Antagonist Naltrexone in Brain Membranes

In synaptosomal membranes from rat brain cortex, in the presence of 150 m M NaC1, the opioid antagonist [ 3 H] naltrexone bound to two populations of receptor sites with affinities of 0.27 and 4.3 n M , respectively. Guanosine-5′-(3-thiotriphosphate) had little modulating effect and did not alter the biphasic nature of ligand binding. On the other hand, receptor-selective opioids differentially inhibited the two binding components of [ 3 H] naltrexone. As shown by nonlinear least-squares analysis, the Μ opioids Tyr-D-Ala-Gly-(Me)Phe-Gly-ol or sufentanil abolished high-affinity [ 3 H] naltrexone binding, whereas the Δ-selective ligands [D- Pen 2 , D-Pen 5 ] enkephalin, ICI 174, 864, and oxymorphindole inhibited and eventually eliminated the low-affinity component in a concentration-dependent manner. These results indicate that, in contrast to the guanine nucleotide-sensitive biphasic binding of opioid-alkaloid agonists, the heterogeneity of naltrexone binding in brain membranes reflects ligand interaction with different opioid-receptor types.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66340/1/j.1471-4159.1991.tb08288.x.pd

Diblock copolymers at a homopolymer-homopolymer-interface: a Monte Carlo simulation

The properties of diluted symmetric A-B diblock copolymers at the interface between A and B homopolymer phases are studied by means of Monte Carlo (MC) simulations of the bond fluctuation model. We calculate segment density profiles as well as orientational properties of segments, of A and B blocks, and of the whole chain. Our data support the picture of oriented ``dumbbells'', which consist of mildly perturbed A and B Gaussian coils. The results are compared to a self consistent field theory (SCFT) for single copolymer chains at a homopolymer interface. We also discuss the number of interaction contacts between monomers, which provide a measure for the ``active surface'' of copolymers or homopolymers close to the interface

Public Benefits of Undeveloped Lands on Urban Outskirts: Non-Market Valuation Studies and their Role in Land Use Plans

Over the past three decades, the economics profession has developed methods for estimating the public benefits of green spaces, providing an opportunity to incorporate such information into land-use planning. While federal regulations routinely require such estimates for major regulations, the extent to which they are used in local land use plans is not clear. This paper reviews the literature on public values for lands on urban outskirts, not just to survey their methods or empirical findings, but to evaluate the role they have played--or have the potential to play-- in actual land use plans. Based on interviews with authors and representatives of funding agencies and local land trusts, it appears that academic work has had a mixed reception in the policy world. Reasons for this include a lack of interest in making academic work accessible to policy makers, emphasizing revealed preference methods which are inconsistent with policy priorities related to nonuse values, and emphasis on benefit-cost analyses. Nevertheless, there are examples of success stories that illustrate how such information can play a vital role in the design of conservation policies. Working Paper 07-2