Alterations in brain antioxidant enzymes and redox proteomic identification of oxidized brain proteins induced by the anti-cancer drug adriamycin: implications for oxidative stress-mediated chemobrain.

Adriamycin (ADR) is a chemotherapeutic for the treatment of solid tumors. This quinone-containing anthracycline is well known to produce large amounts of reactive oxygen species (ROS) in vivo. A common complaint of patients undergoing long-term treatment with ADR is somnolence, often referred to as "chemobrain." While ADR itself does not cross the blood brain barrier (BBB), we recently showed that ADR administration causes a peripheral increase in tumor necrosis factor alpha (TNF-alpha), which migrates across the BBB and leads to inflammation and oxidative stress in brain, most likely contributing to the observed decline in cognition. In the current study, we measured levels of the antioxidant glutathione (GSH) in brains of mice injected intraparitoneally (i.p.) with ADR, as well as the levels and activities of several enzymes involved in brain GSH metabolism. We observed significantly decreased GSH levels, as well as altered GSH/GSSG ratio in brains of ADR treated mice relative to saline-treated controls. Also observed in brains of ADR treated mice were increased levels of glutathione peroxidase (GPx), glutathione-S-transferase (GST), and glutathione reductase (GR). We also observed increased activity of GPx, but a significant reduction in GST and GR activity in mice brain, 72 h post i.p. injection of ADR (20 mg/kg body weight). Furthermore, we used redox proteomics to identify specific proteins that are oxidized and/or have differential levels in mice brains as a result of a single i.p. injection of ADR. Visinin like protein 1 (VLP1), peptidyl prolyl isomerase 1 (Pin1), and syntaxin 1 (SYNT1) showed differential levels in ADR treated mice relative to saline-treated controls. Triose phosphate isomerase (TPI), enolase, and peroxiredoxin 1 (PRX-1) showed significantly increased specific carbonylation in ADR treated mice brain. These results further support the notion ADR induces oxidative stress in brain despite not crossing the BBB, and that antioxidant intervention may prevent ADR-induced cognitive dysfunction.

Detection and quantification of protein adduction by electrophilic fatty acids: mitochondrial generation of fatty acid nitroalkene derivatives.

Nitroalkene fatty acid derivatives manifest a strong electrophilic nature, are clinically detectable, and induce multiple transcriptionally regulated anti-inflammatory responses. At present, the characterization and quantification of endogenous electrophilic lipids are compromised by their Michael addition with protein and small-molecule nucleophilic targets. Herein, we report a trans-nitroalkylation reaction of nitro-fatty acids with beta-mercaptoethanol (BME) and apply this reaction to the unbiased identification and quantification of reaction with nucleophilic targets. Trans-nitroalkylation yields are maximal at pH 7 to 8 and occur with physiological concentrations of target nucleophiles. This reaction is also amenable to sensitive mass spectrometry-based quantification of electrophilic fatty acid-protein adducts upon electrophoretic resolution of proteins. In-gel trans-nitroalkylation reactions also permit the identification of protein targets without the bias and lack of sensitivity of current proteomic approaches. Using this approach, it was observed that fatty acid nitroalkenes are rapidly metabolized in vivo by a nitroalkene reductase activity and mitochondrial beta-oxidation, yielding a variety of electrophilic and nonelectrophilic products that could be structurally characterized upon BME-based trans-nitroalkylation reaction. This strategy was applied to the detection and quantification of fatty acid nitration in mitochondria in response to oxidative inflammatory conditions induced by myocardial ischemia-reoxygenation.

A clinical trial of two conceptually different radical radiotherapy treatments in stage III carcinoma of the cervix.

Two hundred and ninety-six consecutive patients under the age of 70 years and having Stage III carcinoma of the cervix were randomised to receive one of two radical radiotherapy techniques. The first was a small-field, wedged, inhomogeneous 3-week X-ray treatment, followed by two radical radium insertions delivering 80% of a radical intracavity dose. The second was a 4-week homogeneous, large-field X-ray technique, supplemented by a single intracavitary insertion giving 50% of a radical intracavitary dose. Mature 5-year survival rates for the two techniques were 38.6% and 40.3% respectively (p = 0.76). Corrected 5-year results were 44.5% and 45% (p = 0.8). The time to pelvic recurrence and the sites of pelvic recurrence were not significantly different. The rate of major morbidity was eight out of 148 in the first group and five out of 148 in the second. This large, prospective, randomised trial failed to identify any significant advantage to two conceptually different techniques which explored different volumes, fractionation and balance between X-ray therapy and intracavitary therapy. The overall results remain very satisfactory when compared with recently published European results.

Percutaneous absorption of testosterone in the newborn rhesus monkey: comparison to the adult.

Percutaneous absorption of testosterone was determined in newborn rhesus monkeys, an animal model which is relevant to man. Mean percentage of absorptions of 4 and 40 microng/cm2 in the newborn were, respectively, 22.5 +/- 2.2 (SD) and 6.8 +/- 2.1. Statistical comparisons (Student's t-test) of these results with those obtained with adults show no significant difference (P greater than 0.05) in skin penetration of testosternoe in newborn and adult rhesus monkeys. In the newborn, the efficiency of absorption (percentage) decreased when the topical dose was increased 10-fold. However, the total compound absorbed per cm2 area of skin actually increased from 0.9 to 2.7 microng. With one other newborn rhesus, a topical dose of 40 microng/cm2 was applied to the ventral forearm and the area was occluded for 24 hr. Percutaneous absorption was 14.7%, a value twice that from nonoccluded absorption. Systemic absorption from a topical dose becomes critical in the newborn because the ratio of surface area (cm2) to body weight (kilograms) in the newborn is 3 times that in the adult. Given equal application area of skin per newborn and adult, the systemic absorption in the newborn becomes 3 times that of the adult when based on kilograms body weight. With a different ratio of skin surfact to body weight, the therapeutic ratio probably is lower in the newborn than in the adult when the compound is applied topically.

A preliminary trial of doxorubicin in advanced breast cancer and other malignant disease.

Doxorubicin in a dose of 60 mg/m(2) has been used in the treatment of 23 patients with advanced malignant disease, 18 of whom had carcinoma of the breast. The drug has significant clinical activity on its own, prolonged dosage may be required to obtain a response, and there is a risk of cerebral metastases becoming manifest during treatment which is otherwise successful. Cardiac toxicity appears to be acceptably low with this dose regimen.

Cyclophosphamide and nandrolone decanoate in the treatment of advanced carcinoma of the breast--results of a comparative controlled trial of the agents used singly and in combination.

A random trial in which cyclophosphamide, nandrolone decanoate and the two drugs in combination were used in the treatment of advanced breast carcinoma is described. The results suggest that it is preferable to use cyclophosphamide on its own.

A new anti-oestrogenic agent in late breast cancer. An early clinical appraisal of ICI46474.

An introductory clinical trial of the anti-oestrogenic agent IC146474 in late or recurrent carcinoma of the breast is described.Forty-six patients have been treated, of whom 10 have shown a good response. This is of the same order as that seen with oestrogens and androgens.The particular advantage of this drug is the low incidence of troublesome side effects.