Safety and efficacy of using a single agent or a phase II agent before instituting standard combination chemotherapy in previously untreated metastatic breast cancer patients: report of a randomized study--Cancer and Leukemia Group B 8642. (1/228)

PURPOSE: We undertook a prospective, randomized phase III trial to evaluate the safety and efficacy of using a phase II agent before initiating therapy with standard combination chemotherapy in metastatic breast cancer patients. PATIENTS AND METHODS: A total of 365 women with measurable metastatic breast cancer, previously untreated with chemotherapy for their metastatic disease, were randomized to receive either immediate chemotherapy with cyclophosphamide, doxorubicin, and fluorouracil (CAF) or up to four cycles of one of five sequential cohorts of single-agent drugs: trimetrexate, melphalan, amonafide, carboplatin, or elsamitrucin, followed by CAF. RESULTS: The toxicity of each single agent followed by CAF was comparable to that of CAF alone. The cumulative response rates for the single agent followed by CAF were not statistically different from those of CAF alone (44% v 52%; P = .24). However, in the multivariate analysis, patients with visceral disease had a trend toward lower response rates on the phase II agent plus CAF arm (P = .078). Although survival and response duration also were not statistically significantly different between the two study arms (P = .074 and P = .069, respectively), there was a suggestion of benefit for the CAF-only arm. CONCLUSION: The brief use of a phase II agent, regardless of its efficacy, followed by CAF resulted in response rates, toxicities, durations of response, and survival statistically equivalent to those seen with the use of CAF alone. These findings support the use of a new paradigm for the evaluation of phase II agents in the treatment of patients with metastatic breast cancer.  (+info)

Cyclic-imide-hydrolyzing activity of D-hydantoinase from Blastobacter sp. strain A17p-4. (2/228)

The cyclic-imide-hydrolyzing activity of a prokaryotic cyclic-ureide-hydrolyzing enzyme, D-hydantoinase, was investigated. The enzyme hydrolyzed cyclic imides with bulky substituents such as 2-methylsuccinimide, 2-phenylsuccinimide, phthalimide, and 3,4-pyridine dicarboximide to the corresponding half-amides. However, simple cyclic imides without substituents, which are substrates of imidase (ie.g., succinimide, glutarimide, and sulfur-containing cyclic imides such as 2,4-thiazolidinedione and rhodanine), were not hydrolyzed. The combined catalytic actions of bacterial D-hydantoinase and imidase can cover the function of a single mammalian enzyme, dihydropyrimidinase. Prokaryotic D-hydantoinase also catalyzed the dehyrative cyclization of the half-amide phthalamidic acid to the corresponding cyclic imide, phthalimide. The reversible hydrolysis of cyclic imides shown by prokaryotic D-hydantoinase suggested that, in addition to pyrimidine metabolism, it may also function in cyclic-imide metabolism.  (+info)

Dimethyl adipimidate: a new antisickling agent. (3/228)

A new approach to the prevention of sickling in vitro by use of the bifunctional crosslinking reagent, dimethyl adipimidate, is described. Prior treatment of sickle erythrocytes with dimethyl adipimidate will inhibit sickling in completely deoxygenated erythrocytes. Treated erythrocytes do not demonstrate the potassium loss and viscosity increase that usually accompany sickling. The oxygen affinity of hemoglobin in these cells is increased independently from changes in the concentration of 2,3-diphosphoglycerate. The hemoglobin obtained from treated erythrocytes contains a high-molecular-weight component as well as additional positively charged components. The relative degree to which chemical modification and/or crosslinking is an essential part of the antisickling properties of the material is not known.  (+info)

Investigation of the organization of rhodopsin in the sheep photoreceptor membrane by using cross-linking reagents. (4/228)

The organization of rhodopsin in the photoreceptor membrane of sheep rod outer segments was investigated by using a variety of bifunctional reagents. Of the nine reagents used, seven gave oligomeric opsin species, whereas two, copper phenanthroline and dithiobisphenyl azide, failed to cross-link the protein. In general, the cross-linked species obtained showed diminishing yields from dimer to tetramer, together with some higher-molecular-weight aggregates. It is proposed that the patterns of cross-linking arise as a result of collision complexes and best describe a monomeric organization for native rhodopsin. No significant differences between the patterns obtained with dark-adapted bleached or regenerated protein states were observed. This interpretation is discussed in relation to the postulated mechanism of action of rhodopsin.  (+info)

Biphasic effect of bimoclomol on calcium handling in mammalian ventricular myocardium. (5/228)

1. Concentration-dependent effects of bimoclomol, the novel heat shock protein coinducer, on intracellular calcium transients and contractility were studied in Langendorff-perfused guinea-pig hearts loaded with the fluorescent calcium indicator dye Fura-2. Bimoclomol had a biphasic effect on contractility: both peak left ventricular pressure and the rate of force development significantly increased at a concentration of 10 nM or higher. The maximal effect was observed between 0.1 and 1 microM, and the positive inotropic action disappeared by further increasing the concentration of bimoclomol. The drug increased systolic calcium concentration with a similar concentration-dependence. In contrast, diastolic calcium concentration increased monotonically in the presence of bimoclomol. Thus low concentrations of the drug (10 - 100 nM) increased, whereas high concentrations (10 microM) decreased the amplitude of intracellular calcium transients. 2. Effects of bimoclomol on action potential configuration was studied in isolated canine ventricular myocytes. Action potential duration was increased at low (10 nM), unaffected at intermediate (0.1 - 1 microM) and decreased at high (10 - 100 microM) concentrations of the drug. 3. In single canine sarcoplasmic calcium release channels (ryanodine receptor), incorporated into artificial lipid bilayer, bimoclomol significantly increased the open probability of the channel in the concentration range of 1 - 10 microM. The increased open probability was associated with increased mean open time. The effect of bimoclomol was again biphasic: the open probability decreased below the control level in the presence of 1 mM bimoclomol. 4. Bimoclomol (10 microM - 1 mM) had no significant effect on the rate of calcium uptake into sarcoplasmic reticulum vesicles of the dog, indicating that in vivo calcium reuptake might not substantially be affected by the drug. 5. In conclusion, the positive inotropic action of bimoclomol is likely due to the activation of the sarcoplasmic reticulum calcium release channel in mammalian ventricular myocardium.  (+info)

Tethered naphthalene diimide-based intercalators for DNA triplex stabilization. (6/228)

The synthesis and triplex stabilizing properties of oligodeoxyribonucleotides functionalized at the 5'- and/or 3'-termini with a naphthalene diimide-based (NDI) intercalator is described. The NDI intercalator was prepared in a single step from the corresponding dianhydride and was attached to the 5'-terminus of an oligodeoxyribonucleotide following a reverse coupling procedure. The DMT protecting group was removed and the sequence phosphitylated to generate the phosphoramidite derivative on the 5'-terminus of the support-bound oligodeoxyribonucleotide. The NDI intercalator with a free hydroxyl was then added in the presence of tetrazole. Attachment of the NDI to the 3'-terminus relied upon a tethered amino group that could be functionalized first with the naphthalene dianhydride, which was subsequently converted to the diimide. Using both procedures, an oligonucleo-tide conjugate was prepared having the NDI intercalator at both the 5'- and 3'-termini. Thermal denaturation studies were used to determine the remarkable gain in stability for triplexes formed when the NDI-conjugated oligonucleotide was present as the third strand in the complex.  (+info)

A novel amidase (half-amidase) for half-amide hydrolysis involved in the bacterial metabolism of cyclic imides. (7/228)

A novel amidase involved in bacterial cyclic imide metabolism was purified from Blastobacter sp. strain A17p-4. The enzyme physiologically functions in the second step of cyclic imide degradation, i.e., the hydrolysis of monoamidated dicarboxylates (half-amides) to dicarboxylates and ammonia. Enzyme production was enhanced by cyclic imides such as succinimide and glutarimide but not by amide compounds which are conventional substrates and inducers of known amidases. The purified amidase showed high catalytic efficiency toward half-amides such as succinamic acid (K(m) = 6.2 mM; k(cat) = 5.76 s(-1)) and glutaramic acid (K(m) = 2.8 mM; k(cat) = 2.23 s(-1)). However, the substrates of known amidases such as short-chain (C(2) to C(4)) aliphatic amides, long-chain (above C(16)) aliphatic amides, amino acid amides, aliphatic diamides, alpha-keto acid amides, N-carbamoyl amino acids, and aliphatic ureides were not substrates for the enzyme. Based on its high specificity toward half-amides, the enzyme was named half-amidase. This half-amidase exists as a monomer with an M(r) of 48,000 and was strongly inhibited by heavy metal ions and sulfhydryl reagents.  (+info)

Phage Q-beta ribonucleic acid replicase. Subunit relationships determined by intramolecular cross-linking. (8/228)

Phage Qbeta replicase is composed of four subunits of molecular weights 70,000, 65,000, 45,000, and 35,000. Treatment of the enzyme with protein cross-linking reagents results in formation of three covalently bound complexes of molecular weights 215,000, 135,000, and 80,000. Analysis of the two larger complexes formed by cross-linking with a reversible cross-linker (methyl-4-mercaptobutyrimidate) demonstrates that the 215,000 molecular weight complex is composed of one each of the replicase subunits, while the 135,000 molecular weight complex is composed of the two larger subunits. The 80,000 molecular weight complex was shown to be made up of the two smaller subunits by cross-linking these two subunits in the absence of the larger pair. Increasing ionic strength stabilizes the large complex at the expense of the two smaller complexes. The presence of stoichiometric amounts of Qbeta RNA during cross-linking dramatically reduces formation of the large complex; other natural and synthetic RNAs reduce the formation of this complex to a lesser extent.  (+info)