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PubMed1987

Phase I and pharmacokinetic study of trans-N3P3Az2(NHMe)4.

trans-N3P3Az2(NHMe)4, an aziridinyl-substituted cyclophosphazene, was tested for its toxicity, pharmacokinetic behavior, and cytostatic activity in a phase I study in 30 patients. A total of 66 courses of a single iv bolus injection were given in five dose steps. Toxicity consisted of leukocytopenia and thrombocytopenia, dose limiting at 70 mg/m2, mild anemia, and some nausea. Leukocyte and platelet count nadirs fell between 2 and 3 weeks, with recovery at 6 weeks. A tendency for cumulative thrombocytopenia was noticed in three of 13 patients at risk. A three-phase plasma elimination model was applicable with t1/2 alpha of 9.9 minutes, t1/2 beta of 78.5 minutes, and t1/2 gamma of 435.5 minutes; renal drug excretion was substantial. Three partial remissions in 21 evaluable patients suggest some clinical activity for this drug.

Adult↗
PubMed1987

Different effect of two immunomodulating agents cyclosporin A and ciamexon on the insulin metabolism of cultured mouse islets.

Ciamexon is a new immunomodulating agent with promising effects in treatment of newly-diagnosed insulin dependent diabetic patients. Ciamexon seems to have fewer adverse toxic properties than Cyclosporin A. Therefore, the effects of both substances on islet cell function were studied. Collagenase-isolated mouse islets were cultured free-floating for 3 or 7 days in medium RPMI 1640 plus 10% fetal calf serum in the presence of Cyclosporin A or Ciamexon (0.1 microgram/ml, 1 microgram/ml). Culture of the islets in the presence of 0.1 microgram/ml Ciamexon neither reduced the number of viable islets nor impaired insulin secretion as was found in Cyclosporin A. These results should be taken into account when treating early Type 1 diabetes or when transplanting islet cells.

Adjuvants, Immunologic↗
PubMed1987

Multiple lipid interactions of the Sendai virus fusogenic protein.

The membrane topology of the envelope of Sendai virus was investigated using various radioactive photoactivable hydrophobic reagents: 3-(trifluoromethyl)-3-(m-[125I]iodophenyl)diazirine and the two phospholipid analogues, 1-palmitoyl-2-(2-azido-4-nitro)benzoyl-sn -glycero-3- phospho[3H]choline and 1-myristoyl-2,12-amino-(4-N-3-nitro-1-azidophenyl)dodecanoyl-sn-glycero- 3-phospho[14C]choline. The hemagglutinin-neuraminidase glycoprotein and the fusogenic (F) glycoprotein were labeled by all three probes, confirming that these proteins are integral components of the viral envelope. The labeled F glycoprotein, composed of the two subunits F1 and F2, was cleaved in situ with trypsin to yield two fragments, F32 (32 kDa) and F19 (19 kDa). F2 was not labeled by any of the probes, suggesting an external location; whereas F19 was labeled by all probes and hence contains the portion of the F glycoprotein which traverses the viral envelope. Fragment F32 reacted both with 3-(trifluoromethyl)-3-(m-[125I]iodophenyl)diazirine and with 1-palmitoyl-2-(2-azido-4-nitro)benzoyl-sn-glycero-3-phospho[3H]choline, but not with 1-myristoyl-2,12-amino-(4-N-3-nitro-1-azidophenyl)dodecanoyl-sn-glycero- 3- phospho[14C]choline. This result opens the possibility that the F glycoprotein is formed by a loop-like structure having multiple interactions with viral lipids.

Azides↗
PubMed1988

Topography of lactose permease from Escherichia coli.

The topography of lactose permease, in native membrane vesicles and after reconstitution of the purified protein into proteoliposomes, has been investigated by labeling the membrane-embedded portions of the protein using photoactivatable, hydrophobic reagents and by labeling the exposed portions of the protein with water-soluble, electrophilic reagents. Some sites of modification have been localized in fragments of the protein produced by chemical and enzymatic cleavage. These define a number of hydrophilic loops and membrane-spanning regions and give some substance to topographic models of the permease. The N-terminal third of the molecule was labeled by three photoactivatable reagents (3-(trifluoromethyl)-3-m-iodophenyldiazirine and the phospholipid analogues 2-(aceto-(4-benzoylphenylether]-1-palmitoylphosphatidylcholine) and 2-(4-azido-2-nitrophenylaminoacetyl)-1-palmitoylphosphatidylcholin e) as well as the water soluble, electrophilic reagents. The C-terminal part of the molecule is labeled by the diazirine and, to a lesser extent, by the phospholipid analogues. It apparently has more nucleophilic groups accessible to water-soluble reagents than the N-terminal domain, in which the density of apparently unreactive ionizable residues proved to be unexpectedly high. The apparent lack of reactivity of some of these residues may be explained either by their being buried in the protein moiety within the membrane domain, or by their close association with other ionizable residues on the surface of the protein.

Azirines↗
PubMed1988

Potential anti-tumour 2,5-bis (1-aziridinyl)-1,4-benzoquinones: relationship between cytotoxicity against DNA-repair deficient E. coli, inactivation of bacteriophage M13mp19, and in vitro and in vivo anti-tumour activity.

A series of reductively activated 3,6 substituted 2,5-bis(aziridinyl)benzoquinones, designed as potential anti-tumour agents, was shown to interact with DNA. This was assayed by studying the colony forming ability of DNA-repair deficient E. coli K12 and the inactivation of bacteriophage M13mp19. The activities of the compounds as measured in the two assays show a good correlation. Reduction of the quinone compounds is essential for activity in the two assays. Reduction activates opening of the aziridine ring and formation of an alkylating species. The results suggest that steric factors are important in DNA adduct formation. Methylation of the aziridine rings decreases the activity. Bulky 3,6-substitutes also decrease the activity. No correlation is found between above-mentioned assays for DNA modification and in vivo activity towards tumour cells. It is possible that, as well as DNA, other cellular targets are involved. A correlation is observed between the DNA modifying activity and toxicity against L1210 cells in vitro. The relative high activity against L1210 cells of bromine substituted compounds is possibly related to alternative mechanisms in which bromine acts as an efficient leaving group.

Animals↗
PubMed1986

[Differing progress patterns in cancer of the uterine cervix and variant effects of adjuvant chemotherapy based on histological type].

Clinical features of 644 surgically treated cases of cancer of the uterine cervix were analyzed according to their histological type. Large cell non-keratinizing carcinomas (L) showed node metastasis proportional to the grade of invasion in the cervix, and the lowest recurrence rate. Small cell non-keratinizing carcinomas (S) tended to have widely spread metastasis from an early stage of the primary lesion. Lateral recurrence from metastatic foci was common in this type. Keratinizing carcinomas (K) were localized in the cervix until the primary tumor became enlarged to a certain size. Central recurrence from invasive foci in the surrounding tissue or organ occurred more often than lateral recurrence in this type. Metastasis pattern of pure adenocarcinomas (A) was similar to that of S, but recurrence was delayed. Adenosquamous carcinomas (AS) showed a similar metastasis pattern to that of K, but recurrence was rapid and the ratio high. Prophylactic maintenance chemotherapy with Tegafur (800 mg/day) or Carboquone (0.5 mg/day) was performed in 187 cases for a period of 2 years after surgery. The effect of maintenance chemotherapy depended on the histological type. A marked effect was obtained in the groups of S and A, in which no recurrence has appeared so far. The recurrence rate of L dropped to 1/5 that of the control. However, unsatisfactory results were shown in the groups of K and AS including the keratinizing cell component. It is of significance that maintenance chemotherapy showed the highest effectiveness in S and A on which conventional adjuvant therapy, i.e. postoperative radiotherapy, has had the least effect. This has led us to consider that a proper selection of adjuvant therapies would contribute toward improving the postoperative prognosis of patients with cancer of the uterine cervix.

Adenocarcinoma↗
PubMed1986

Interaction of the cytoskeletal component vinculin with bilayer structures analyzed with a photoactivatable phospholipid.

The cytoskeletal component vinculin has been proposed to act as an actin-plasma membrane linker. In order to demonstrate a possible direct interaction of vinculin with bilayers, photolabeling with a phospholipid generating a highly reactive carbene was used. This phosphatidylcholine analogue (1-palmitoyl-2-[10-[4-[(trifluoromethyl)diazirinyl]phenyl]-[3H] 9-oxaundecanoyl]-sn-glycero-3-phosphocholine), with the photoactivatable diazirine group on its apolar portion, has been shown to label selectively membrane-embedded domains of membrane proteins. Vinculin is significantly labeled upon incubation and photolysis with liposomes containing trace amounts of this photoactivatable phospholipid, but only when the liposomes also contain acidic phospholipids. Labeling of vinculin is markedly increased (5-17-fold) by all acidic phospholipids tested so far (30%, w/w), compared to labeling in neutral phospholipids. Labeling is high at low ionic strength, but significant vinculin labeling can still be observed at physiological salt concentrations and acidic phospholipid content of the membrane. Our results provide evidence that vinculin inserts into the hydrophobic part of the bilayer by interacting with acidic phospholipids. A similar interaction may be of importance in vivo.

Actins↗
PubMed1986

Modulation in vitro of immune parameters in homosexual males with the preclinical complex of symptoms related to acquired immune deficiency syndrome by azimexon.

In search of potential therapeutic agents for the acquired immunodeficiency syndrome (AIDS) among homosexual males, we studied in vitro the immunorestorative effect of azimexon in patients with this syndrome. Since a reduction in the ratio between helper inductor and suppressor/cytotoxic T-cell subsets (OKT-4/OKT-8) seems to be the hallmark of the syndrome, we measured azimexon-induced numerical changes in T-cell subsets and correlated them with changes in a simultaneously tested T-cell function as measured by the xenogeneic local graft-versus-host reaction (GVHR). Following incubation of peripheral blood mononuclear cells from 10 homosexual subjects with 10 micrograms/ml of azimexon at 37 degrees C for 1 h, the median number of T cells defined by the OKT-8 phenotype declined from 0.6 X 10(3) to 0.33 X 10(3)/mm3 (p less than 0.02), resulting in an increase in the OKT-4/OKT-8 ratio from 0.65 to 1.37 (p less than 0.01). There were no numerical changes in T cells defined by OKT-3 and OKT-4 phenotypes. Similar decreases in OKT-8-defined T cell occurred among eight heterosexual controls. The restoration of the OKT-4/OKT-8 ratio among the homosexual subjects was associated with a significant improvement in their T-cell function. Thus, the median volume of the local GVHR increased from 38.2 to 63.5 mm3 (p less than 0.02). Parallel changes in OKT-4/OKT-8 ratio and changes in local GVHR following incubation with azimexon were observed. These results suggest that azimexon may be an important immunorestorative agent. Clinical trials with this agent in patients with AIDS or its preclinical complex of symptoms seem warranted.

Acquired Immunodeficiency Syndrome↗
PubMed1986

Hydrophobic binding domains of rat intestinal maltase-glucoamylase.

Rat intestinal microvillus maltase-glucoamylase was isolated by detergent extraction and purification in the presence of protease inhibitors as previously described and incorporated into phospholipid vesicles. After purification of the vesicles on Sephadex G-50, maltase was labelled with 3-trifluoromethyl-3-(m-[125I]iodophenyl) diazirine ([125I]TID) by photolysis using a water-jacketed mercury vapour lamp with a saturated CuSO4 filter. The labelled enzyme was extracted with acetone, resuspended in 1% Triton X-100, reincorporated into phospholipid vesicles, and digested with activated papain to release the hydrophilic polar head of the enzyme from the vesicle bilayer. Vesicle-bound and free enzyme components were separated on Sepharose 4B. Ninety percent of the enzymatic activity was free, while a similar percentage of radioactive label remained with the vesicles in keeping with the separation of an active polar headpiece from a labelled apolar peptide in the lipid bilayer. The vesicle fractions were subjected to chromatography on Sephadex LH-60 with ethanol--formic acid (7:3) as the eluant. A single radioactive peak (14 kilodaltons (kDa)) was separated from labelled lipid. Sodium dodecyl sulfate--polyacrylamide gel electrophoresis of the peak showed a radioactive doublet of 26-28 kDa, possibly representing a dimer. No other labelled peptides were found. These results suggest that detergent-solubilized maltase-glucoamylase is inserted into the phospholipid bilayer via an apolar peptide with a minimum molecular mass of 14 kDa. The peptide probably represents a terminal anchor segment of the 145-kDa subunit which is converted to 130 kDa when the membrane-bound enzyme is solubilized by papain.

Affinity Labels↗
PubMed1987

[The structure of products of modification of nucleotides and DNA by ethyleneimine and thio-TEPA].

Previously undescribed products of dGMP, GMP, AMP, dCMP and TMP aminoethylation by ethylenimine and N,N',N"-triethylenethiophosphoamide (thio-TEPA) have been obtained and shown to be aminoethyl esters of nucleotides with the free or substituted amino group. In case of dGMP and GMP ethylenimine and tio-TEPA alkylate not only phosphate but also the base residue at the N7 position. The 7-aminoethyl derivatives of dGMP and GMP, which thio-TEPA afforded, were characterized whereas the corresponding ethylenimine derivatives are decomposed under alkaline conditions in the course of the isolation. Possible reasons of extreme instability of these compounds are given. For the first time the ability of thio-TEPA to alkylate DNA at position 7 of guanine residue is shown by means of the luninescence method.

Alkylation↗
PubMed1988

[Effect of interferon on the number of cytogenetic disorders occurring in human cultured lymphocytes treated with thio-TEPA and fotrin].

The paper deals with the modifying effects of natural (leukocytic) and synthesized (recombinant) interferons on the number of cytogenetic injuries in the cultured lymphocytes of human peripheric blood after exposure to alkylating chemicals--thio-TEPA and fotrin. The analysis of chromosomal aberration levels is suggestive of a significant protective effect exerted by interferons. The addition of the recombinant interferon increased the number of sister chromatid exchanged frequency in mutagen treated variants. The application of the test system that involves two types of interferon made it possible to reveal differences in their cytogenetic effect during the protector-sensitive period of cultivation.

Aziridines↗
PubMed1985

Contact allergy to aziridine paint hardener.

A painter experienced an extensive dermatitis when exposed to a paint primer (undercoating) used to protect wood siding. The primer was an acrylic emulsion with a polyfunctional aziridine added as a self-curing cross-linker or hardener. The polyfunctional aziridine cross-linker was made by reacting propyleneimine with a polyfunctional acrylate, trimethylolpropane triacrylate (TMPTA). Our patient reacted to the cross-linker and also reacted to TMPTA, which is present in excess in the cross-linker. He also cross-reacted to pentaerythritol triacrylate (PETA). Both TMPTA and PETA can be used in the production of aziridine hardeners and both are well known as sensitizers in radiation-dried acrylic printing inks and coatings.

Acrylates↗
PubMed1988

[Modification of the effect of fotrin in phenobarbital-induced metabolic system].

Random bred male rats were given drinking water with phenobarbital (PB) (daily doses 0.4; 2 and 10 mg/kg) during 120 days. Activity of mixed function of oxygenases (content of cytochromes P-450) were enhanced after PB treatment in doses 2 and 10 mg/kg. Following PB treatment the animals were injected 5-times ethyleneimine derivate--fotrin at the doses 2, 4 and 7 mg/kg. The induction of mixed function of oxygenases resulted in significant decrease in the number of cells with chromosome aberrations.

Animals↗
PubMed1988

Azimexone and cysteine hydrazide in the treatment of allergic encephalomyelitis.

In the course of allergic encephalomyelitis (EAE) in chickens, azimexone suppressed the production of the specific IgM immunoglobulins. Moreover, it decreased the level of haptoglobin and sialic acid but stimulated the activity of antitrypsin. It was also observed to reduce the production of the plasmatic cells in the spleen. L-cysteine hydrazide hydrochloride decreased the level of sialic acid in EAE; intensified the activity of trypsin inhibitor and exerted no effect upon the level of antimyelin antibodies.

Animals↗