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PubMed2004

Polyglutamation of methotrexate with common polymorphisms in reduced folate carrier, aminoimidazole carboxamide ribonucleotide transformylase, and thymidylate synthase are associated with methotrexate effects in rheumatoid arthritis.

OBJECTIVE: Methotrexate (MTX) enters cells through the reduced folate carrier (RFC-1) and exerts part of its effects through polyglutamation to MTX polyglutamates (MTXPGs) and inhibition of 5-aminoimidazole-4-carboxamide ribonucleotide transformylase (ATIC) and thymidylate synthase (TS). We investigated the contribution of common genetic polymorphisms in RFC-1 (G80A), ATIC (C347G), and TS (28-bp tandem repeats located in the TS enhancer region [TSER*2/*3]) and of MTXPGs to the effect of MTX in patients with rheumatoid arthritis. METHODS: The study was cross-sectional. All patients received MTX for at least 3 months. The numbers of tender and swollen joints, the Visual Analog Scale (VAS) scores for the physician's global assessment of disease activity, and the modified Health Assessment Questionnaire scores were collected. Using the VAS score for the physician's assessment of patient's response to MTX, the population of patients was dichotomized into responders to MTX (VAS score < or =2 cm) and nonresponders to MTX (VAS score >2 cm). A pharmacogenetic index was calculated as the sum of homozygous variant genotypes (RFC-1 AA + ATIC 347GG + TSER *2/*2) carried by the patients. MTXPG concentrations were measured in red blood cells (RBCs) by high-performance liquid chromatography. RESULTS: The dose of MTX was not associated with the effects of MTX (P > 0.05). In contrast, increased RBC long-chain MTXPG concentrations (median 40 nmoles/liter; range <5-131 nmoles/liter) and an increased pharmacogenetic index were associated with a lower number of tender and swollen joints (P < 0.05) and a lower score for the physician's global assessment of disease activity (P < or = 0.001). Patients with RBC MTXPG levels of >60 nmoles/liter and carriers of a homozygous variant genotype were 14.0-fold (95% confidence interval [95% CI] 3.6-53.8) and 3.7-fold (95% CI 1.7-9.1), respectively, more likely to have a good response to MTX (P <or = 0.01). CONCLUSION: These data suggest that measuring RBC MTXPG levels and/or the common polymorphisms in the folate-purine-pyrimidine pathway may help in monitoring MTX therapy.

Adult↗
PubMed2002

A molecular dynamics study of the stoichiometric complex formed by poly (alpha, L-glutamate) and octyltrimethylammonium ions in chloroform solution.

We present a molecular dynamics simulation at 300 K in explicit solvent environment of chloroform of the stoichiometric complex formed by poly(alpha,L-glutamate) and octyltrimethylammonium ions. We observed that the alpha-helix conformation of the polypeptide chain remains stable during a 2-ns run. The surfactant ions predominantly adopted an extended conformation that is stabilized by favorable interactions with the organic solvent. Analysis of the organization of the surfactant with respect to the polypeptide chain indicated that each octyltrimethylammonium cation was preferentially bound to more than one carboxylate group. It was found that the most populated arrangement was that with the surfactant cations interacting with two carboxylate groups simultaneously.

Cations↗
PubMed1990

Hydration effects on dynamics of polyglycine and sodium poly(L-glutamate).

Solid state nmr methods were applied to the study of the motions and structural heterogeneity in polyglycine, sodium poly(L-glutamate), and poly(L-alanine). The response of both the main-chain and side-chain resonances to the addition of water was studied using static and magic-angle sample-spinning line shapes as well as the carbon spin-lattice relaxation times, the proton spin-lattice relaxation time in the rotating frame, and the proton-carbon cross-polarization time. The polyglycine motions are not drastically affected by the addition of water when the polymer is in the 3(1)-helix or the beta-sheet structure. The sodium poly(L-glutamate), however, responds to increased hydration with little motion in the main-chain carbon atoms, but considerable flexibility of the side-chain atoms. The greatest motions are reported for the C5 carbon with rotational amplitudes about the C4-C5 bond of about of 50 degrees. In addition, motions somewhat less than half this size are required closer to the main chain.

Peptides↗
PubMed1992

Salt bridge induced changes in the secondary structure of ionic polypeptides.

The carboxylate-containing homopolypeptides poly(L-glutamate) [poly(Glu)] and poly(L-aspartate) [poly(Asp)] were found to form different types of ordered structures in the presence of poly(L-lysine) [poly(Lys)]. Mixing poly(Glu) with poly(Lys) in aqueous solution at neutral pH results in the instantaneous formation of a gel-like precipitate. The secondary structure of the gel precipitate can be best described as intermolecular antiparallel beta-strands, involving the backbone amide groups, as evidenced by the presence of characteristic amide I bands in the ir spectrum at 1684 and 1612 cm-1. Mixing poly(Asp) with poly(Lys) under identical conditions results in the formation of a fine precipitate with a different morphology. Examination of the ir spectrum of the precipitate revealed that unlike poly(Glu), poly(Asp) did not yield any discrete secondary structure upon precipitation with poly(Lys). Addition of solutions containing Ca2+ or Mg2+ to the poly(Glu)/poly(Lys) aggregates resulted in complete dissolution of the gel, with the disappearance of the ir bands characteristic of the intermolecular hydrogen-bonded network. The results demonstrate the importance of salt bridges in establishing strong hydrogen bonds between the backbone amide groups. Reaggregation occurred upon heating the poly(Glu)/poly(Lys) mixture in the presence of Ca2+, but not in the presence of Mg2+ ions. In the presence of Ca2+ ions, aggregation and formation of an extended hydrogen-bonded network occurred upon heating. The aggregates formed upon heating poly(Glu)/poly(Lys) in the presence of Ca2+ were attributed solely to complexation of Ca2+ to the carboxylate groups of poly(Glu) with poly(Lys) remaining free in solution. Dissolution of the aggregate could be accomplished through addition of Mg2+ at room temperature.

Calcium↗
PubMed2005

alpha-Helical polypeptide microcapsules formed by emulsion-templated self-assembly.

alpha-Helical peptide microcapsules were prepared by the emulsion-templated self-assembly of amphiphilic poly(gamma-benzyl L-glutamate)s (PBLG) 1. By mixing solutions of 1 in dichloromethane (in the form of a sodium salt) with water, oil-in-water emulsions were obtained. Spontaneous stripping of the dichloromethane phase caused a decrease in the diameter of the microdroplets and finally stable microcapsules formed. The microcapsules contain an inner aqueous phase as observed by confocal laser scanning microscopy (CLSM). Binding of hydrophobic pyrene molecules to the polypeptide shell was also demonstrated. The present polypeptide microcapsules are stable even after drying in air and they would serve as supramolecular vehicles for both hydrophobic and water-soluble molecules.

Capsules↗
PubMed1993

Monensin-sensitive cellular events modulate neurite extension on laminin: an example of higher-order regulation of cell motility.

NG108-15 cells extend "rapid-onset" neurites vigorously within the first hour after plating in minimal serum-free medium on Petri dishes coated with polylysine and laminin (1 ng/mm2). We recently reported that the initial rates of neurite formation and cell translocation are further accelerated in this system when non-specific substratum attachment sites are partially blocked by polyglutamate, bovine serum albumin, or polyethylene glycol polymers [Smalheiser, N. R. (1991): Dev. Brain Res. 62:81-89]. When cells were plated in the presence of the monovalent cation ionophore monensin (1-5 microM) or hypertonic sucrose (50-100 mM), the initial rate of outgrowth on laminin/polylysine-treated Petri dishes was not affected, yet the acceleration produced by polyglutamate was strongly inhibited. These data indicate that monensin-sensitive intracellular events can regulate neurite extension on laminin indirectly, through modulating the effects exerted on cells by nonspecific substratum sites. Although the critical events affected by monensin remain to be identified, movements of laminin receptors (their clustering, internalization, and recycling) are likely targets for further study.

Anti-Bacterial Agents↗
PubMed1995

Polylysine cross-links axoplasmic neurofilaments into tight bundles.

We have used axoplasm from the squid giant axon to investigate the effects of anionic and cationic polypeptides on the mobility and organization of axonal neurofilaments (NFs). Intact cylinders of axoplasm were extruded from squid giant axons into an excess volume of artificial axoplasm solution. In a previous study on the mobility of NFs in extruded axoplasm, we showed that these polymers disperse freely and diffusively into the surrounding solution, thereby expanding the axoplasmic cross-sectional area [Brown and Lasek, 1993: Cell Motil. Cytoskeleton 26:313-324]. In the present study, we found that 83nm-long ("long-chain") polylysine, a synthetic multivalent cationic protein, inhibited the radial expansion of isolated axoplasm and condensed the axoplasm, thereby reducing the cross-sectional area. Equivalent concentrations of a 7nm-long ("short-chain") polylysine did not inhibit the expansion of axoplasm by long-chain polylysine was dependent on the polylysine concentration; condensation of axoplasm was observed at concentrations of 0.01 mg/ml (0.27 microM) or greater. Electron microscopy of the condensed axoplasm showed that the NFs were aligned side-by-side and in parallel in closely-packed bundles. Equivalent concentrations of 91 nm-long ("long-chain") polyglutamate, a synthetic multivalent anionic protein, partially inhibited the expansion of axoplasm but did not cause the NFs to bundle and did not cause the axoplasm to condense. These studies indicate that cationic proteins bind tightly to the highly charged anionic surfaces of NFs and can link them together into compact bundles in a charge-dependent and length-dependent manner. The tightly packed organization of these cross-linked NFs differs from the normal loose organization of NFs in healthy axons. However, tightly bundled NFs are sometimes found in certain neuropathologies, such as giant axonal neuropathy.

Animals↗
PubMed1993

Pharmacokinetics and biological responses after treatment of the rat R-1 rhabdomyosarcoma with methotrexate.

Time relationships of drug concentrations in tissue of a transplantable rat rhabdomyosarcoma and of tumour responses up to 120 hr after treatment with methotrexate (MTX) were analysed and compared. MTX was shown to be retained within the tumour in a substantial concentration for several days, although no evidence of MTX polyglutamation was obtained. The response data confirm that MTX is active in the tumour for up to at least 3 days after injection. Within the first day after MTX treatment the nucleotide pools are only partly depleted. This indicates that the inhibition of DNA synthesis is still incomplete at the time when salvage precursors in increasing amounts are becoming available from decaying cells. From flow cytometric analysis of cell-cycle progression it is concluded that subsequent cohorts arriving in early S-phase were retarded, but not inhibited, in their progression through the S phase. At 3 days after MTX treatment the mean rate of cell-cycle progression as well as the relative clonogenic capacity were maximally reduced to 30% and 1% of control values, respectively. From 3 to 5 days the rate of cell-cycle progression was gradually restored, whereas from day 5 onwards the clonogenic capacity increased at a high rate corresponding to the proliferation rate of exponentially growing rhabdomyosarcoma cells in culture. However, a continuous reduction of cell recovery lasting for at least 12 days after treatment contributed to an 8-day delay in tumour volume growth.

Animals↗
PubMed1983

High-performance liquid chromatographic analysis of MTX, 7-OH-MTX and MTX derivatives: application to intracellular metabolism in tumor cells (HT 29).

In order to study the intracellular metabolism of Methotrexate (MTX) and the cytotoxicity of the antifolates, a specific paired-ion HPLC method has been developed which permits the simultaneous determination of DAMPA, MTX, 7-OH-MTX, MTX-G1, MTX-G2 and MTX-G3. Cells were incubated with 3H-MTX. The MTX metabolites were extracted, purified on SEP-PAK cartridges and further analysed by high-performance liquid chromatography (HPLC). The stationary phase was constituted by a C18 muBondapak and the mobile phase by 5 mM phosphate buffer (pH 7.4) containing 2.5 mM tetrabutylammonium nitrate. The elution was performed with a linear methanol gradient (20--30%). HPLC fractions were collected and radioactivity evaluated by beta counting (retention times: DAMPA = 12.93 min; MTX = 18.29 min; 7-OH-MTX = 21.13 min; MTX-G1 = 22.69 min; MTX-G2 = 26.81 min; MTX-G3 = 30.61 min). This analytical procedure was applied to separate and characterize multiple forms of MTX polyglutamate derivatives in HT 29, a human adenocarcinoma cell line varying the incubation time (4--18 h) and MTX concentration (0.6--10.6 micrometer). The incorporation process seems to be characteristic of a cell line resistant to MTX. The incorporation were very low and after a 4-h exposure time only 5% of the MTX was converted to polyglutamates. Between 1.6 and 10.6 microM MTX, no difference was observed in the polyglutamization. The defect in the incorporation of the drug and in the metabolization process in vitro could partially explain the failure of the MTX treatment in colorectal cancer.

Adenocarcinoma↗
PubMed1985

Wetting characteristics and blood clotting on surfaces of copoly(gamma-Benzyl-L-glutamate, gamma-hydroxyethyl-L-glutamine).

The film surface of poly(gamma-benzyl-L-glutamate) (PBLG) was modified with 2-aminoethanol to enhance its hydrophilicity. Controlling the reaction conditions of PBLG and 2-aminoethanol, various types of copoly(gamma-benzyl-L-glutamate, gamma-hydroxyethyl-L-glutamine) film surfaces were obtained. Surface free energy (gamma sv), the dispersive component of gamma sv (gamma dsv), the nondispersive component of gamma sv (gamma psv), and the interfacial free energy of polymer surface with water (gamma sw), which were obtained by using the contact angle measurement and calculation method proposed by Andrade et al., were changed remarkably by the aminolysis. The gamma sv value increased after 2 h of aminolysis from 48.2 (PBLG) to 65.3 dyn/cm and gradually increased to around 70 dyn/cm after 12 h reaction. (gamma dsv) and (gamma psv) changed from 31.0 and 17.2 dyn/cm (PBLG) to 26.5 and 44.3 dyn/cm, respectively. These parameters of the material surfaces, modified over 12 h reaction, were found to be similar to those of the surfaces of canine aorta, vein, and human fibrin membrane. Blood clotting times on these polymer surfaces were comparatively longer than on siliconized glass surfaces.

Blood Coagulation↗
PubMedDate not supplied

Microheterophase structure, permeability, and biocompatibility of A-B-A triblock copolymer membranes composed of poly(gamma-ethyl L-glutamate) as the A component and polybutadiene as the B component.

A-B-A block copolymers (EBE) consisting of poly(gamma-ethyl L-glutamate) as the A component and polybutadiene as the B component were synthesized. The microheterophase structure of these block copolymers, as observed microscopically, was less distinct than that of the block copolymer (GBG) composed of poly(gamma-benzyl L-glutamate) as the A component. This was attributed to the better compatibility of the ethyl group with polybutadiene block, compared with the benzyl group. The observed micelle size of various microheterophase structures ranged from 350 to 480 A, which agreed well with the micelle size estimated from a thermodynamic study. From the measurement of water permeation through the EBE block copolymer membranes, the contributions of the interfacial region between the alpha-helical polypeptide domain and polybutadiene domain to the permeability coefficient were concluded to be higher than those of poly(gamma-methyl L-glutamate)-polybutadiene block copolymer (MBM) membranes, i.e., more hydrophilic domain seemed to exist in EBE membranes than in MBM membranes. The results of in vivo tests on the tissue compatibility indicate that the EBE block copolymer membranes have good biocompatibility.

Animals↗
PubMed1987

Macromolecular attachment as a metabolic stabilizer for a labile radiosensitizer.

4-Nitro-5-sulfonylimidazoles represent a class of hypoxic cell radiation sensitizers whose in vitro activity greatly exceeds that of the current clinical standard, misonidazole. However, in vivo studies with these 4,5-disubstituted imidazoles have shown that a rapid reaction with circulating thiols decomposes the agent and compromises its clinical utility. Drug-macromolecule conjugates prepared in this study from poly-L-glutamate, succinylated poly-L-lysine, dextran, and a succinylated polylysine-antibody, all demonstrated protection of the drug from glutathione displacement. 1-Methyl-4-nitro-5-imidazolyl 4-aminophenyl sulfone conjugated to a succinylated poly-L-lysine-antibody was greater than 7 times less reactive than the unbound drug. Polymer transport may offer a useful tumor-delivery mechanism for these highly reactive radiation sensitizers.

Antibodies, Monoclonal↗
PubMed2006

Effects of thermoresponsive coacervation on the hydrolytic degradation of amphipathic poly(gamma-glutamate)s.

Hydrolytic properties of thermoresponsive biopolymers with amphiphilic structures, gamma-PGA-P, were investigated. Hydrolysis was monitored in terms of molecular weight changes using GPC and spectroscopic measurements. The hydrolytic degradation of gamma-PGA-P was controlled by a change in the degree of propyl group conversion, reaction temperature, and/or reaction pH. The degradation was classified as the rapid elimination of propyl side chains and the moderate cleavage of peptide linkages in the backbone. Furthermore, hydrophobic environments established by the thermoresponsive coacervation of gamma-PGA-P60 solutions inhibited hydrolytic degradation reactions. Inversely, hydrolytic degradations increased coacervation temperatures. Kinetic studies of hydrolytic reactions suggest that the degradation rate of gamma-PGA-P60 solutions can be controlled by their thermoresponsivity. The hydrolysis reported here represents the first degradation rate controlled by thermoresponsive coacervation.

Hydrogen-Ion Concentration↗