PURPOSE: We performed a phase I/II dose-escalation trial of cyclophosphamide, mitoxantrone, and 5-fluorouracil (CNF) in combination with human recombinant granulocyte-colony-stimulating factor (G-CSF, filgrastim) in patients with advanced breast cancer. The objectives of this trial were (1) to gain experience with filgrastim given to patients with advanced breast cancer and receiving standard-dose CNF, and (2) to determine the maximum tolerated dose of CNF that could be given with filgrastim support by incremental dose escalation of two components of the CNF regimen, cyclophosphamide and mitoxantrone. METHODS: Four patients who had received prior therapy for advanced disease received standard-dose CNF with filgrastim support. Sequentially enrolled patients who had received no prior chemotherapy for advanced disease were treated with standard-dose CNF without filgrastim (5 patients), standard-dose CNF with filgrastim (15 patients), or were entered into sequential cohorts of 3-6 patients to be treated with increasing doses of CNF with filgrastim support (29 patients). RESULTS: The maximum tolerated doses that could be given with filgrastim support were 1500 mg/ml cyclophosphamide, 20 mg/m2 mitoxantrone, and 500 mg/m2 5-FU. Overall, 7 complete (14%) and 13 partial responses (26%) were observed. Despite the use of filgrastim, repeated cycles of CNF at doses of 2000 mg/m2 cyclophosphamide, 25 mg/m2 mitoxantrone, and 500 mg/m2 5-FU could not be given because of neutropenia and thrombopenia. Among 18 patients with bidimensionally measurable disease there were 3 complete (17%) and 5 partial (28%) responses. The median progression-free survival of all patients was 236 days (34 weeks). CONCLUSION: The use of filgrastim allows CNF to be given at approximately twice the dose intensity of "standard"-dose CNF. Because nonhematopoietic toxicity was not dose-limiting, further dose escalation of this regimen might be possible with more effective hematopoietic support. The response rate and survival of patients treated in this study were within the range expected with standard-dose chemotherapy.

Adult↗

PubMedDate not supplied

Flow-flash, time-resolved resonance Raman spectroscopy of the oxidation of reduced and of mixed valence cytochrome oxidase by dioxygen.

Time-resolved resonance Raman spectroscopy has been used to study the reduction of oxygen by both reduced and mixed valence cytochrome oxidase. Laser flash photodissociation of CO from the carbon monoxy complex of the enzyme, after this species had been rapidly mixed with oxygenated buffer, was used to initiate the reaction for both forms of the enzyme. The CO photolysis product of the mixed valence enzyme contains cytochrome a3+ and cytochrome a3(2+) in its unligated form. This species reacts with O2 in the first few microseconds to form a photolabile intermediate which has Raman frequencies characteristic of oxygenated heme. This indicates that an oxyhemoglobinlike complex of oxygen with a3(2+) is the precursor to oxygen reduction. A similar intermediate is detected in the fully reduced enzyme reaction. In the mixed valence oxidase system, the oxy intermediate is replaced by a nonphotolabile species in which a3 is oxidized with t1/2 approximately equal to 200 musec. These results demonstrate the feasibility of applying time-resolved vibrational techniques to irreversible electron transfer reactions and, in particular, elucidate some of the transient species in the cytochrome oxidase/O2 system.

Carbon Monoxide↗

PubMedDate not supplied

Under-coding in Australia limits the performance of DRG groupers.

The Diagnosis Related Group (DRG) system is now used extensively in Australia to classify acute inpatients for many applications, including payments to hospitals. The quality of the inpatient separation data affects the performance of the DRG version, especially its predictive validity. Data from the State of Maryland, in the United States, contain more secondary diagnosis and procedure codes than Australian data. A comparison of the performance of DRG versions using data from Australia and Maryland allowed us to answer the following research question: What impact did these additional codes have on the performance of the DRGs? The best performance in predictive validity (R2) was obtained using the Maryland data no matter which DRG version was used. Casemix-adjusted code counts showed that more diagnoses were coded in Maryland. The most plausible reason for this was that conditions were not being recorded comprehensively by doctors in the medical record in Australia.

Abstracting and Indexing↗

PubMedDate not supplied

Anomalous reduction of cytochrome b in highly purified complex III from baker's yeast.

In highly purified bc1-complex from baker's yeast, the reduction of cyt c1 and partial reduction of cyt b is obtained by catalytic amount of succinate dehydrogenase and succinate in the presence of 7 microM antimycin. After the addition of ferricyanide the c1 is re-oxidized and a increase in the reduction of b is observed. Using stopped-flow we established that the oxidation of c1 by ferricyanide proceeds as a pseudo-first order reaction and the reduction of b is faster and with two phases. Our observation suggests that these two processes are not directly interconnected and that other component than c1 must be the "control factor" in the anomalous reduction of cyt b. This component must be, by exclusion, the iron-sulfur protein.

Cytochrome b Group↗

PubMedDate not supplied

Midwives' journal. Who needs advertising?

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Advertising↗

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Substrate-induced free radicals in prostaglandin H synthase.

Reaction of ovine PGH synthase with arachidonic acid or hydroperoxides produces several tyrosine radical species that can be distinguished by electron paramagnetic resonance (EPR) spectroscopy. We have correlated the temporal sequence of the EPR signals with optical changes of the heme center, and with product formation. The synthase was reconstituted with either heme (Fe-PGHS) or Mn protoporphyrin IX (Mn-PGHS). Incubation of Fe-PGHS with equimolar arachidonate resulted in rapid appearance of a wide doublet tyrosyl radical EPR signal (34 G peak-to-trough); the intensity was near maximal by 7 s. The doublet gave way over the next 10 s to a wide singlet (32 G peak-to-trough) which peaked at 46 s and then decayed slowly. Electronic absorbance spectra indicated that formation of peroxidase Compound I was complete within 1 s; accumulation of peroxidase Compound II paralleled accumulation of the wide doublet tyrosyl radical. PGG2 and PGH2 accumulated rapidly during the first 5 s of reaction; little arachidonate remained after 12 s. The tyrosyl radical giving the wide doublet EPR signal is thus the best candidate for the oxidizing species postulated to abstract the 13S hydrogen atom from arachidonate during cyclooxygenase catalysis by Fe-PGHS. Incubation of Mn-PGHS with arachidonate also led to rapid generation of an oxidized peroxidase cycle intermediate, a protein-linked free radical, and prostaglandins. The radical signal seen with Mn-PGHS (singlet, 36 G peak-to-trough) was distinct from those observed with Fe-PGHS, but the kinetics of the Mn-PGHS radical were consistent with participation in cyclooxygenase catalysis.

Animals↗