Structural studies of the methylated, acidic polysaccharide associated with coccoliths of Emiliania huxleyi (Lohmann) Kamptner

For the structure analysis of the methylated, acidic polysaccharide associated with the coccoliths of the alga Emiliania huxleyi (Lohmann) Kamptner, the native, the carboxyl-reduced, and the desulphated, carboxyl-reduced polysaccharides have been submitted to methylation analysis. Graded hydrolysis with acid, uronic acid degradation, and periodate oxidation/partial hydrolysis with acid in conjunction with methylation analysis were also applied. The results of the various degradation procedures have led to a proposed structure for the average unit of the polysaccharide. The mannan backbone consists of at least 80% of (1¨3)-linked D-mannosyl residues and has many side-chains. The mannan backbone carries ester-bound sulphate groups, terminal D-ribosyl or L-arabinosyl groups, and short side-chains of two or three D-galactosyluronic acid residues. There is also a complex side-chain composed of D-xylose and L-rhamnose, wherein the branched rhamnosyl residues are substituted by 3-O-methyl-D-xylose, 2,3-di-O-methyl-L-rhamnose, a di-(D-galactosyl-uronic acid)-D-xylosyl unit, and an oligosaccharide. The oligosaccharide is composed of 2,3-di-O-methyl-L-rhamnose, 3-O-methyl-D-galacturonic acid, 6-O-methyl-L-mannose, D-galacturonic acid, L-mannose, and L-rhamnose

Structural analysis of acidic oligosaccharides derived from the methylated, acidic polysaccharide associated with coccoliths of Emiliania huxleyi (lohmann) kamptner

A series of acidic oligosaccharides was obtained by graded, acid hydrolysis of the methylated, acidic polysaccharide associated with the coccoliths of the alga Emiliania huxleyi (Lohmann) Kamptner. After fractionation by ion-exchange chromatography, the structures of the oligosaccharides were determined by sugar analysis, g.l.c.-m.s. of the intact, permethylated oligosaccharide-alditols, and methylation analysis. The following oligosaccharides were characterised: α--GalpA-(1→6)-α--Manp-(1→3)--Man, -GalpA-(1→4)--GalpA-(1→6)-Man, -GalpA-(1→4)--GalpA-(1→2/6)-Manp-(1→3)-Man, -GalpA-(1→4)--GalpA-(1→3)--Xyl, -GalpA-(1→2)--Manp6Me-(1→4)--GalpA-(1→2)--Rha, -GalpA-(1→2)-Manp-(1→4)--GalpA-(1→2)--Rha, -GalpA-(1→2)--Rhap-(1→4)--GalpA-(1→2)--Rha, -GalpA-(1→2)--Manp6Me-(1→4)--GalA, -GalpA-(1→2)-Manp-(1→4)--GalA, -GalpA-(1→2)--Manp6Me-(1→4)--GalpA-(1→2)--Man6Me, -GalpA-(1→2)--Manp6Me-(1→4)--GalpA-(1→2)-Man, -GalpA3Me-(1→2)--Manp6Me-(1→4)--GalpA-(1→2)--Man6Me, and -GalpA3Me-(1→2)--Manp6Me-(1→4)--GalA

Effect of cisplatin exposure on platinum accumulation and growth inhibition in human neoplastic and normal squamous epithelial cells of the mucosa of the upper-aerodigestive tract

The aim of the present study was to investigate how normal head and neck epithelial cells (NHNEC) respond to cisplatin compared to their neoplastic counterparts with respect to intracellular platinum (Pt) levels and growth inhibition. A colorimetric assay was used to assess growth inhibition after exposure to cisplatin for 72 h. Growth inhibition did not differ between cultures of neoplastic (n=5) and normal cells (n=5). Intracellular Pt levels, determined with atomic absorption spectroscopy were about 30-fold higher in the normal epithelial cells. The main finding of this study is that normal epithelial cells from the head and neck region have a much higher tolerance for cisplatin than their neoplastic counterparts. Interestingly, this characteristic is without consequence for growth inhibition. Copyright (C) 1999 Elsevier Science Ireland Ltd

Composition of a methylated, acidic polysaccharide associated with coccoliths of Emiliania huxleyi (Lohmann) Kamptner

The water-soluble, acidic polysaccharide isolated from the coccoliths of the alga Emiliania huxleyi (Lohmann) Kamptner contains residues of the following sugars: L-galactose, D-glucose, D-mannose, L-mannose, L-rhamnose, L-arabinose, D-ribose, D-xylose, 6-O-methyl-D-mannose, 6-O-methyl-L-mannose, 2,3-di-O-methyl-L-rhamnose, 3-O-methyl-D-xylose, and D-galacturonic acid. L-Mannose, 6-O-methyl-D-mannose, 6-O-methyl-L-mannose, and 2,3-di-O-methyl-L-rhamnose are novel constituents of a polysaccharide. In addition, the presence of sulphate groups was found. Galacturonic acid and sulphate in the polysaccharide bind Ca2+ ions apparently in a ratio of one mol of Ca2+ per mol of acidic residue. This feature is relevant for the proposed matrix function of the polysaccharide in the formation of the calcified cell-wall plates (coccoliths) of the alga

Pharmacokinetics of cisplatin with and without amifostine in tumour- bearing nude mice

Amifostine (Ethyol, WR-2721) is in use in the clinic as a protector against platinum-induced toxicities. We have previously reported that amifostine induced a potentiation of the antitumour activity of carboplatin in human ovarian cancer xenografts. An influence of amifostine on the pharmacokinetics of carboplatin, resulting in higher platinum concentrations in plasma and tissues of the tumour-bearing nude mice, was thought to be the cause of enhancement of the antitumour activity. Therefore, the pharmacokinetics of cisplatin were investigated in tumour-bearing nude mice treated with cisplatin alone or in combination with amifostine. A significant increase in the area under the curve (AUC) of the total platinum concentration in mice treated with amifostine was only observed in the kidney (from 355 to 398 nmol h/g), whereas in the other tissues and plasma no significant changes were measured. The selective protection of normal tissues by amifostine was confirmed by a decrease in the AUC of the cisplatin-DNA adduct levels in normal tissues. The decrease was only significant in the Hver (282-240 fmol h/μg DNA), whereas in tumour tissue a slight increase in the AUC of the cisplatin-DNA adducts could be detected (91.3-110.1 fmol h/μg DNA). The minor influence of amifostine on the pharmacokinetics of cisplatin may be the reason why amifostine did not potentiate the antitumour activity of cisplatin. The influence of amifostine on cisplatin-DNA adduct levels in normal tissues versus tumour tissues is further evidence for the usefulness of this toxicity modulator in cancer patients

Influence of amifostine on the pharmacokinetics of cisplatin in cancer patients

The pharmacokinetics of cisplatin was investigated in 13 patients receiving 18 courses of cisplatin alone or in combination with amifostine to investigate the influence of amifostine (WR 2721; Ethyol) on the pharmacokinetics of cisplatin. Cisplatin was administered as a 1-h i.v. infusion, whereas amifostine was given i.v. over 15 min just before the cisplatin infusion. An increase in the final half-life of ultrafilterable platinum was observed after treatment with cisplatin and amifostine (t( 1/4 ), 0.77 ± 0.10 h; n = 8), compared to cisplatin alone (t( 1/4 ), 0.57 ± 0.15 h; n = 8). This might be caused by an influence of amifostine on the kidney function, because an increase in the serum creatinine levels was also observed 24 h after treatment with cisplatin and amifostine (13.8 ± 12.6%; n = 9), which was not observed after treatment with cisplatin alone (-0.1 ± 6.8%; n = 9). Surprisingly, the final half-life of unchanged cisplatin did not increase, but even showed a slight decrease after treatment with amifostine. In vitro data would suggest that this might be due to a chemical interaction between cisplatin and amifostine. Because the AUC values of ultrafilterable platinum and unchanged cisplatin did not change significantly and no change in Pt-DNA adduct (Pt-GG) levels in leukocytes was observed upon addition of amifostine in the treatment schedule, the change in the pharmacokinetics of cisplatin is most probably of minor importance and has no significant impact on the efficacy of cisplatin, as already confirmed by clinical studies

Pharmacokinetics of carboplatin with and without amifostine in patients with solid tumors

We showed previously that amifostine (WR 2721; Ethyol), a protector against carboplatin-induced toxicities, changed the pharmacokinetics of carboplatin in tumor-bearing nude mice. In the present study, the influence of amifostine on the pharmacokinetics of carboplatin was studied in patients when carboplatin was given in combination with three doses of amifostine, administered just before the carboplatin infusion and 2-4 h thereafter. Compared with a control group of patients who received carboplatin alone, the patients receiving the combination had a longer final half-life of ultrafilterable platinum species [5.0 h versus 3.5 h in patients with a normal creatinine clearance (Clcr > 80 ml/min); 5.6 h versus 4.2 h in those with an impaired renal function (50 < Clcr < 80 ml/min)]. This might be caused by an influence of amifostine on the renal clearance of carboplatin as suggested by a transient increase in serum creatinine levels 24 h after treatment in the patients receiving the combination (mean ± SD: 34.1% ± 17.2% versus - 1.8% ± 16.5% in patients treated with carboplatin alone). The impact of these changes on the area under the concentration-time curves of the ultrafilterable platinum species was hardly noticeable in patients with a normal renal function but led to a significant increase in patients with an impaired renal function (395 ± 59 pmol/l·h versus 280 ± 62 μmol/l·h in patients receiving carboplatin alone). The clinical relevance of this influence is unclear, although theoretically it may result in an increase in the efficacy of carboplatin, as has been observed in tumor-bearing nude mice