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At least 145 records · Page 8Linked to original sources
PubMed2001

Phase I trial of ifosfamide and 24-h infusional paclitaxel in pelvic malignancies: a Gynecologic Oncology Group study.

OBJECTIVE: The goal of this work was to develop a combination chemotherapy regimen consisting of ifosfamide and paclitaxel to be evaluated in the management of gynecologic malignancies. METHODS: The Gynecologic Oncology Group conducted a Phase I trial of the regimen, initially with paclitaxel (24-h infusion) delivered on Day 1 and ifosfamide (1 h) administered (with Mesna) over the subsequent 4 days. All patients received granulocyte colony-stimulating factor (G-CSF) starting 24 h after the Day 5 chemotherapy. Treatment was repeated on a 28-day schedule. A cohort of patients also received the alternate sequence of ifosfamide (4 days) followed by paclitaxel. RESULTS: Twenty-two patients were evaluated. Even at the lowest dose level tested (paclitaxel 135 mg/m(2) followed by ifosfamide 1 g/m(2)/day x 4 days) grade 4 neutropenia was almost universal, despite the routine use of G-CSF. The alternate drug administration sequence resulted in marrow suppression of similar severity. CONCLUSION: The combination of 24-h infusional paclitaxel with ifosfamide delivered over 4 days results in severe neutropenia, despite the administration of G-CSF, and is not recommended for further evaluation. In view of the known activity of the two agents in several malignancies, including cervix cancer, it would be reasonable to investigate the delivery of the agents employing alternative treatment schedules predicted to result in less severe marrow suppression (e.g., 3-h infusional paclitaxel).

Adult↗
PubMed1996

Inhibition and catalytic mechanism of HIV-1 aspartic protease.

The structure of the HIV-1 protease in complex with a pseudo-C2 symmetric inhibitor, which contains a central difluoroketone motif, has been determined with X-ray diffraction data extending to 1.7 A resolution. The electron density map clearly indicates that the inhibitor is bound in a symmetric fashion as the hydrated, or gemdiol, form of the difluoroketone. Refinement of the complex reveals a unique, and almost symmetric, set of interactions between the geminal hydroxyl groups, the geminal fluorine atoms, and the active-site aspartate residues. Several hydrogen bonding patterns are consistent with that conformation. The lowest energy hydrogen disposition, as determined by semiempirical energy calculations, shows only one active site aspartate protonated. A comparison between the corresponding dihedral angles of the difluorodiol core and those of a hydrated peptide bond analog, calculated ab-initio, shows that the inhibitor core is a mimic of a hydrated peptide bond in a gauche conformation. The feasibility of an anti-gauche transition for a peptide bond after hydration is verified by extensive molecular dynamics simulations. The simulations suggest that rotation about the C-N scissile bond would readily occur after hydration and would be driven by the optimization of the interactions of peptide side-chains with the enzyme. These results, together with the characterization of a transition state leading to bond breakage via a concerted exchange of two protons, suggest a proteolysis mechanism whereby only one active site aspartate is initially protonated. The steps of this mechanism are: asymmetric binding of the substrate; hydration of the peptidic carbonyl by an active site water; proton translocation between the active site aspartate residues simultaneously with carbonyl hydration; optimization of the binding of the entire substrate facilitated by the flexible structure of the hydrated peptide bond, which, in turn, forces the hydrated peptide bond to assume a gauche conformation; simultaneous proton exchange whereby one hydroxyl donates a proton to the charged aspartate, and, at the same time, the nitrogen lone pair accepts a proton from the other aspartate; and, bond breakage and regeneration of the initial protonation state of the aspartate residues.

Binding Sites↗
PubMed1995

Allergen-induced glycoconjugate secretion in guinea-pig trachea in vivo: modulation by indomethacin, BW B70C and ZD-2138.

A method has been established for measurement of tracheal secretions in anaesthetized, ventilated guinea-pigs. The upper trachea was cannulated and perfused with saline. The perfusate was analysed for protein using the Lowry assay and for glycoconjugates ('mucus') by a procedure generating a fluorophore from fucose moieties in the sample. Intravenously infused acetylcholine (ACh) stimulated an increase in glycoconjugate secretion which was maximal after 75 min of ACh administration. Total protein concentration was not increased. Intravenously infused 15-HETE produced a similar increase in glycoconjugate secretion also without increasing protein concentration, but the time of maximal effect was earlier (30 min) than with ACh. Intravenous infusion of allergen (ovalbumin) in antihistamine pretreated, sensitized animals induced a dose-related glycoconjugate secretion which was maximal at 30 min after challenge. Indomethacin potentiated allergen-induced glycoconjugate secretion. The reportedly specific inhibitor of 5-lipoxygenase, ZD-2138, substantially inhibited allergen-induced pulmonary bronchoconstriction but did not influence glycoconjugate secretion. In contrast, the selective 5-, 15-lipoxygenase inhibitor BW B70C significantly attenuated both allergic airway closure and glycoconjugate secretion. These studies demonstrate the practicability of measuring glycoconjugate secretion in guinea-pig trachea in vivo, and that ACh and 15-HETE are potent secretagogues in this species. Further, they suggest that allergic glycoconjugate secretion is mediated, at least in part, via the release of lipid mediators from pathways other than via 5-lipoxygenase.

Acetylcholine↗
PubMed1991

Actin dynamics studied by solid-state NMR spectroscopy.

Solid-state nuclear magnetic resonance spectroscopy was used to study the motion of 2H and 19F probes attached to the skeletal muscle actin residues Cys-10, Lys-61 and Cys-374. The probe resonances were observed in dried and hydrated G-actin, F-actin and F-actin-myosin subfragment-1 complexes. Restricted motion was exhibited by 19F probes attached to Cys-10 and Cys-374 on actin. The dynamics of probes attached to dry cysteine powder or F-actin were very similar and the binding of myosin had little effect indicating that the local probe environment imposes the major influence on motion in the solid state. Correlation times determined for the solid state probes indicated that they were undergoing some rapid internal motion in both G-actin and F-actin such as domain twisting. The probe size influenced the motion in G-actin and appeared to sense monomer rotation but not in F-actin where segmental mobility and intramonomer co-ordination appeared to dominate.

Acetone↗
PubMed1986

Arginyl residues and thermal stability in proteins.

Guanidination and amidination of bovine serum albumin, yeast enolase and yeast alcohol dehydrogenase were accompanied by increases in thermal stability at lower extents of modification. Decreases in thermal stability result from greater modification. These results support suggestions that surface guanidino groups (arginyl groups) are an important factor in thermal stability of proteins.

Alcohol Dehydrogenase↗
PubMed1985

Induction of a cytochrome P-450-dependent fatty acid monooxygenase in Bacillus megaterium by a barbiturate analog, 1-[2-phenylbutyryl]-3-methylurea.

In previous publications from our laboratory, we reported that a soluble, cytochrome P-450-dependent fatty acid monooxygenase from Bacillus megaterium ATCC 14581 can be induced by phenobarbital and a variety of other barbiturates. The tested barbiturates showed an excellent correlation between increasing lipophilicity and increasing inducer potency (Kim BH, Fulco AJ; Biochem Biophys Res Commun 116: 843-850, 1983). The only exception proved to be mephobarbital (N-methylphenobarbital) which, although more lipophilic than phenobarbital, is not an inducer of fatty acid monooxygenase activity. We have now found that 1-[2-phenylbutyryl]-3-methylurea (PBMU), an acylurea that can be derived from mephobarbital by hydrolytic cleavage of the barbiturate ring, is an excellent inducer of this activity. Paradoxically, the addition of mephobarbital to the bacterial growth medium containing PBMU significantly enhances the apparent potency of the acylurea to induce fatty acid monooxygenase activity as measured in cell-free extracts. When cell-free extracts of cells grown separately in PBMU or mephobarbital are mixed no enhancement of activity is seen. This finding suggests that the effect of mephobarbital is to somehow increase the efficiency of PBMU as an inducer of the P-450-dependent fatty acid monooxygenase rather than to induce an activator of this enzyme or a rate-limiting component of the monooxygenase system. Finally, both mephobarbital and PBMU induce the synthesis of total cytochrome P-450 in B. megaterium although PBMU is a much more potent P-450 inducer. For cytochrome P-450 induction, however, there is no synergistic or even additive effect when mephobarbital and PBMU are used together in the bacterial growth medium.

Bacillus megaterium↗
PubMed1982

The partial protective effect of the hydroxyl radical scavenger dimethyl urea on streptozotocin-induced diabetes in the mouse in vivo and in vitro.

The protective effect on streptozotocin-induced diabetes of dimethyl urea, a hydroxyl radical scavenger, has been evaluated in vivo and in vitro. Pretreatment with dimethyl urea before a single diabetogenic dose of streptozotocin partially protected NMRI mice from hyperglycaemia, whereas the serum glucose of C57BL/KsJ mice increased during week 2 of observation. When the pancreases of these latter mice were examined histologically, insulitis was found in 15 out of 22 animals. The protective effect of dimethyl urea in the NMRI mice was not due to short-term hyperglycaemia induced by the drug, since pretreatment with glucose did not protect from streptozotocin but potentiated its diabetogenic effect. Dimethyl urea reduced the inhibition caused by streptozotocin on proinsulin biosynthesis of NMRI islets in vitro. It is suggested that streptozotocin-induced diabetes in mice may involve generation of hydroxyl radicals which are toxic to islet B cells. If this immediate cytoxicity is reduced by a scavenger, a more slowly developing hyperglycaemia and an accompanying insulitis may occur in particularly susceptible animals.

Animals↗
PubMed1984

Protection by dimethyl urea against hyperglycaemia, but not insulitis, in low-dose streptozotocin-induced diabetes in the mouse.

The protective effect of dimethyl urea, a hydroxyl radical scavenger, against low-dose streptozotocin-induced diabetes has been evaluated. Dimethyl urea was given to C57BL/KsJ mice before five daily injections of streptozotocin. The saline pre-treated control animals became gradually hyperglycaemic, whereas the dimethyl urea treated group remained normoglycaemic during the 11 week follow-up period. Two weeks after the first streptozotocin injection, six out of ten dimethyl urea-treated and 12 out of 15 saline-treated mice had insulitis. Four or 11 weeks after the streptozotocin treatment, insulitis was rare in both groups. Multiple injections of dimethyl urea only did not affect the serum glucose concentrations or the islet morphology. It is suggested that dimethyl urea protected against hyperglycaemia by reducing the beta-cell cytotoxic effects of the low doses of streptozotocin. An increased number of cells would thus be preserved and the animals less prone to develop diabetes, despite the presence of an inflammatory process in the pancreatic gland.

Animals↗
PubMed1984

Mechanisms of streptozotocin- and alloxan-induced damage in rat B cells.

In studies to evaluate possible inhibitors of the B-cell toxin, streptozotocin, the superoxide scavenger, superoxide dismutase, did not prevent or reduce the toxic effects of streptozotocin as determined by loss of insulin secretion from rat pancreatic B cells in monolayer culture. However, 1,1-dimethyl urea, a scavenger of the hydroxyl radical, did afford significant protection. Both scavengers diminished the cytotoxic effects of alloxan. The inhibitors of poly (ADP-ribose) synthetase, 3-aminobenzamide and nicotinamide, also were effective in attenuating alloxan- and streptozotocin-induced B-cell toxicity. Tests of the hydroxyl-scavenging ability of the three streptozotocin antagonists revealed that 3-aminobenzamide, nicotinamide and 1,1-dimethyl urea were effective scavengers of this free radical. Conversely, 1,1-dimethyl urea, although not as potent as 3-aminobenzamide or nicotinamide, was found to inhibit poly (ADP-ribose) synthetase. These data indicate that these chemicals most likely attenuate alloxan-induced toxicity by scavenging the hydroxyl radical and diminish streptozotocin-induced toxicity by inactivation of the poly (ADP-ribose) system.

Alloxan↗
PubMed1983

Streptozotocin, but not alloxan, induces DNA repair synthesis in mouse pancreatic islets in vitro.

In the present investigation, the abilities of streptozotocin and alloxan to induce DNA repair synthesis in isolated mouse pancreatic islets have been compared using an autoradiographic technique. Streptozotocin exposure in vitro induced a dose-dependent DNA repair synthesis, whereas no such effect was observed after alloxan treatment. The hydroxyl radical scavenger dimethyl urea and the poly(ADP-ribose) synthetase inhibitors nicotinamide and theophylline reduced the streptozotocin-induced DNA repair. The results suggest that the initial events in streptozotocin-induced B cell injury are DNA damage and repair and that alloxan exerts its major cytotoxic effect by a different mechanism.

Alloxan↗
PubMed1975

The effect of inhibitors on the electron flow triggering photo-phobic reactions in Cyanophyceae.

1. Since photo-phobic reactions in the blue green alga Phormidium uncinatum seem to be triggered by changes of electron flow rates into or out of an electron pool situated in the electron transport chain between photo-system II and I, the effect of inhibitors affecting the electron transport chain has been studied. 2. Dose response curves of the phobic reaction have been measured by varying the trap energy in double beam light trap experiments with constant pairs of monochromatic light. From these dose response curves the effects of the inhibitors on both types of phobic reactions, i.e. exit reactions and entrance reactions, have been calculated. 3. Dibromothymoquinone (DBMIB) inhibits the electron transport between the electron pool and photosystem I by preventing the reoxidation of plastoquinone. The phobic entrance reaction, which results in an emptying of the light trap, is triggered by changes in the electron flow out of the pool; thus it is more effected by DBMIB than the exit reaction, which is mediated by the electron transport into the pool. 4. The phobic exit reaction, which results in accumulations in the light trap, is triggered by changes in the electron flow into the electron pool via photosystem II. 3-(3,4-dichlorophenyl)-1,1-dimethylurea (DCMU) inhibits the electron transport near photosystem II; thus it affects the exit reaction more than the entrance reaction.

Cell Movement↗