Reduction of breast lymphoedema secondary to breast cancer: a randomised controlled exercise trial.

BACKGROUND: Breast lymphoedema can occur following surgical treatment for breast cancer. We investigated whether an exercise program reduced breast lymphoedema symptoms compared to a non-exercise control group. METHODS: A single-blinded randomised controlled trial was conducted in which women with stable breast lymphoedema (n = 89) were randomised into an exercise (n = 41) or control (n = 47) group. The intervention comprised a 12-week combined aerobic and resistance training program, supervised weekly by an accredited exercise physiologist. All participants completed a weekly symptoms diary and were assessed monthly to ensure that there was no exacerbation of their lymphoedema. Changes in the breast were captured physically with ultrasound and bioimpedance spectroscopy and changes in symptoms were captured using European Organization for Research and Treatment of Cancer (EORTC) Breast Cancer (BR23) and Lymphoedema Symptom Intensity and Distress questionnaires. RESULTS: The exercise group reported a greater reduction in breast-related symptoms than the control group, assessed by the EORTC BR23 breast symptom questions. Measures of extracellular fluid, assessed with bioimpedance spectroscopy ratio, decreased in the exercise group compared to the control group. No significant difference was detected in dermal thickness in the breast, assessed by ultrasound. Session attendance in the exercise sessions was high, with two musculoskeletal adverse events reported, but no exacerbations of lymphoedema observed. CONCLUSION: Combined resistance and aerobic exercise training is safe for women living with breast lymphoedema. Preliminary data suggest exercise training can reduce breast lymphoedema symptoms to a greater extent than usual care.

The relationship between BPAQ-derived physical activity and bone density of middle-aged and older men.

UNLABELLED: The bone-specific physical activity questionnaire (BPAQ) accounts for activities that affect bone but has not been used in studies with older adults. Relationships exist between the BPAQ-derived physical activity and bone density in healthy middle-aged and older men but not men with prostate cancer. Disease-related treatments detrimental to bone should be considered when administering the BPAQ. INTRODUCTION: The bone-specific physical activity questionnaire (BPAQ) was developed to account for bone-specific loading. In this retrospective study, we examined the relationship between BPAQ-derived physical activity and bone mineral density (BMD) in middle-aged and older men with and without prostate cancer. METHODS: Two groups, 36 healthy men and 69 men with prostate cancer receiving androgen suppression therapy (AST), completed the BPAQ and had whole body, total hip, femoral (FN) and lumbar spine BMD assessed by dual-energy X-ray absorptiometry. RESULTS: Past (pBPAQ), current (cBPAQ) and total BPAQ (tBPAQ) scores for the healthy men were related to FN BMD (pBPAQ r = 0.36, p = 0.030; cBPAQ r s = 0.35, p = 0.034; tBPAQ r = 0.41, p = 0.014), and pBPAQ and tBPAQ were related to total hip (r s = 0.35, p = 0.035 and r s = 0.36, p = 0.029, respectively) and whole body BMD (r s = 0.44, p = 0.007 and r s = 0.45, p = 0.006, respectively). In men with prostate cancer, the BPAQ was not significantly associated with BMD. In stepwise regression analyses, body mass and tBPAQ predicted 30 % of the variance in total hip BMD (p = 0.003), cBPAQ predicted 14 % of the variance in FN BMD (p = 0.002), and body mass, age and tBPAQ predicted 47% of the variance in whole body BMD (p < 0.001) in healthy men. In men with prostate cancer, the BPAQ was not an independent predictor of BMD. CONCLUSIONS: Although BPAQ-derived estimates of physical activity are related to bone status in healthy middle-aged and older men, the adverse effect of AST on bone appears to obscure this relationship in men with prostate cancer.

Short-term oral 3-hydroxypyridin-4-one dosing increases aluminum excretion and partially reverses aluminum-induced toxicity in the rabbit independent of chelator lipophilicity.

The objectives of the present study were to determine the efficacy and toxicity of repeated oral administration of 3-hydroxypyridin-4-one (HP) chelators in a rabbit model of aluminum (Al) accumulation and toxicity, and the influence of chelator lipophilicity on these effects. Efficacy was assessed as chelator-induced Al mobilization and excretion and reversal of Al accumulation and Al-induced toxicity. Chelator-induced toxicity was assessed by multiple measures. Six HPs were given orally 12 times over 1 month to Al-loaded rabbits, which had significant elevation of Al in most tissues and evidence of Al-induced nephrotoxicity, osteomalacia, and anemia. Intravenous desferrioxamine (DFO), the current chelator of choice for the treatment of Al-overload and toxicity, was included as a positive control. All six HPs and DFO demonstrated efficacy evidenced by significantly greater urinary and biliary Al elimination after the twelfth dose than seen in saline-treated controls. All of the HPs were more effective than DFO. Chelator-induced urinary Al excretion accounted for 58-98% of total (urinary plus biliary) Al excretion. Chelator-facilitated Al excretion was nearly complete within 12 hr, demonstrating a fairly short duration of action in rabbits with intact renal function. HP treatments did not consistently affect tissue concentrations of Al or other metals. However, there was a trend toward chelator-induced reduction of Al-induced nephrotoxicity. The influence of HP lipophilicity was limited to a positive correlation between HP x Al lipophilicity and biliary Al output and a negative correlation between HP and HP x Al lipophilicity and reduction of Kupffer cell Al. Little toxicity was evident after repeated oral HP dosing. Adrenal weight increased after treatment with several HPs. There was a decrease in testes weight after several HPs, which is consistent with an antiproliferative effect. More frequent dosing and/or a longer duration of HP treatment might produce greater reversal of the Al-induced toxicity and perhaps reveal more adverse effects than seen in this study. There was a lack of profound toxicity during this short-term study. The 1,2-dimethyl (CP20) and 1,2-diethyl (CP94) HPs, which have been the most extensively studied HPs, were the least effective of the HPs examined. These results encourage the further investigation of other HPs as oral alternatives to DFO for the treatment of Al accumulation and toxicity.

The 3-hydroxypyridin-4-ones more effectively chelate aluminum in a rabbit model of aluminum intoxication than does desferrioxamine.

This study was conducted to assess the influence of lipophilicity on the in vivo aluminum (Al) chelation activity of 3-hydroxypyridin-4-ones (HPs). Chelation activity was evidenced as increased Al elimination in an animal model of Al accumulation and toxicity. The subjects were Al-loaded rabbits. A non-Al-loaded group was included to characterize the rabbit model of Al intoxication. Eight HPs and desferrioxamine (DFO), the drug currently used to treat Al intoxication, were studied. Chelation activity was determined from quantitative biliary and urinary Al excretion and serum Al determinations conducted for 24 hr after DFO or HP intravenous administration, compared with saline. Toxicity was evaluated by observation, blood biochemistry assays, hematological evaluation, gross necropsy, and histopathological assessment of the liver. Al loading produced nephrotoxicity, hepatotoxicity, and anemia. Each of the chelators mobilized Al into serum. The efficiency of Al chelation, calculated from 24-hr biliary plus urinary Al output, ranged from 2.8 to 11.7% for the HPs, compared with 2.1% for DFO. Urinary Al excretion accounted for 78-98% of total Al excretion. Nearly all of the chelator-facilitated Al excretion occurred within 8 hr of dosing. Al chelation efficacy did not correlate with HP or HP Al lipophilicity; however, increasing HP lipophilicity increased the biliary fraction of the excreted Al. There was no evidence for toxicity after HP dosing, other than the previously shown ability of one of the HPs to produce seizures. The greater chelation efficacy of the HPs than DFO provides advantages over DFO. The lack of toxicity after a single dose of all but the most lipophilic HP encourages their further evaluation as orally effective chelators.

Oxidative metabolism of 1-(2-chloroethyl)-3-alkyl-3- (methylcarbamoyl)triazenes: formation of chloroacetaldehyde and relevance to biological activity.

(Methylcarbamoyl)triazenes have been shown to be effective cancer chemotherapeutic agents in a number of biological systems. Because of their chemical stability, it is likely that their activity in vivo is the result of a metabolic activation process. Previous studies have shown that 1-(2-chloroethyl)-3-methyl-3-(methylcarbamoyl)triazene (CMM) and 1-(2-chloroethyl)-3-benzyl-3-(methylcarbamoyl)triazene (CBzM) are metabolized by rat liver microsomes in the presence of NADPH to yield the ((hydroxymethyl)carbamoyl)triazene analogs of the parent compounds. The present studies show that both compounds are also oxidized at the chloroethyl substituent to yield chloroacetaldehyde and a substituted urea. In the case of CBzM metabolism, 47% of the metabolized parent compound was recovered as benzylmethylurea, 8% was recovered as benzylurea, and 26% was recovered as the ((hydroxymethyl)carbamoyl)-triazene and carbamoyltriazene metabolites. These results suggest that the chloroethyl group is the favored initial site of metabolism. In reaction mixtures containing initial concentrations of 300 microM CBzM, 78 microM chloroacetaldehyde was produced, as compared to 58 microM chloroacetaldehyde produced from the metabolism of 300 microM CMM. The formation of chloroacetaldehyde, a known mutagenic DNA alkylating agent, may explain the biological activity of these compounds.

An unexpected pathway for the metabolic degradation of 1,3-dialkyl-3-acyltriazenes.

In the presence of NADPH, rat liver microsomes catalyzed the degradation of a series of 1,3-dialkyl-3-acyltriazenes, and the extent of the reaction was correlated with compound lipophilicity. In the case of two methylcarbamoyltriazenes, 1-(2-chloroethyl)-3-benzyl-3- (methylcarbamoyl)triazene (CBzM) and 1-(2-chloroethyl)-3-methyl-3-(methylcarbamoyl)triazene (CMM), microsomal metabolites were isolated. Identification of the CBzM metabolites as 1-(2-chloroethyl)-3-benzyl-3-(hydroxymethylcarbamoyl)triazene and 1-(2-chloroethyl-3-benzyl-3-carbamoyltriazine, and the CMM metabolite as 1-(2-chloroethyl)-3-methyl-3-(hydroxymethylcarbamoyl)triazene indicated that the first metabolic step involves hydroxylation of the methylcarbamoyl substituent. Detailed studies of the metabolism of CBzM indicated that the Km for the reaction was 84 microM, and that metabolism was more efficient if microsomes were prepared from male than from female rats. During prolonged incubation, the metabolites of CBzM were also degraded. The degradation of CBzM and its metabolites was inhibited by SKF-525A and metyrapone, suggesting the involvement of a cytochrome P450 isozyme, and supporting the hypothesis that the process is oxidative rather than hydrolytic in both cases. Metabolic oxidation represents an alternative pathway to chemical or enzymatic hydrolysis for the in vivo decomposition of (methylcarbamoyl)triazenes. This mechanism may ultimately explain the antitumor efficacy and low acute toxicity of selected compounds.