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Global ischemia after cardiac arrest, intraoperative hypoxia/hypotension, and hemorrhagic shock causes brain injury resulting in severe neurological and neurobehavioral deficits. Neurodegeneration can be prevented by local aromatase expression, and estrogen synthesis can be neuroprotective in ischemia/reperfusion. Therefore, aromatase, the enzyme that transforms androgens to estrogens, may be a potential target for the study of reperfusion injury after brain ischemia. We investigated the expression of aromatase and C/EBPβ using western blotting in rat hippocampus after transient global ischemia plus hypotension. Immunohistochemical analysis was performed for aromatase. After 10min of ischemia, aromatase and C/EBPβ expression in cytosolic extracts were observed after 10min and 24h of reperfusion. The expression of both proteins was similar in control and damaged tissues. Immunoblot analysis demonstrated that the highest aromatase expression appeared in damaged hippocampi after 1week and was gradually reduced after 2-10weeks. C/EBPβ expression increased at 1week in nuclear extracts of damaged hippocampi. The aromatase inhibitor megestrol acetate (20mg/kg/day) suppressed aromatase and nuclear C/EBPβ levels in ischemic hippocampi. Our findings indicate that ischemia as well as chronic neurodegenerative processes leads to an increase in cytoplasmic aromatase and nuclear C/EBPβ. Thus, it is possible to hypothesize an interaction between this enzyme gene and transcription factor., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Objective: In April 2005 a phase III randomized study was started to establish which was the most effective and safest treatment of cancer-related anorexia/cachexia syndrome and oxidative stress in improving identified primary endpoints: increase of lean body mass, decrease of resting energy expenditure (REE), increase of total daily physical activity, decrease of interleukin-6 and tumor necrosis factor-alpha, and improvement of fatigue assessed by the Multidimensional Fatigue Symptom Inventory-Short Form (MFSI-SF)., Methods: All patients were given as basic treatment polyphenols plus antioxidant agents alpha-lipoic acid, carbocysteine, and vitamins A, C, and E, all orally. Patients were then randomized to one of the following five arms: 1) medroxyprogesterone acetate/megestrol acetate; 2) pharmacologic nutritional support containing eicosapentaenoic acid; 3) L-carnitine; 4) thalidomide; or 5) medroxyprogesterone acetate/megestrol acetate plus pharmacologic nutritional support plus L-carnitine plus thalidomide. Treatment duration was 4 mo. The sample comprised 475 patients., Results: By January 2007, 125 patients, well balanced for all clinical characteristics, were included. No severe side effects were observed. As for efficacy, an interim analysis on 125 patients showed an improvement of at least one primary endpoint in arms 3, 4, and 5, whereas arm 2 showed a significant worsening of lean body mass, REE, and MFSI-SF. Analysis of variance comparing the change of primary endpoints between arms showed a significant improvement of REE in favor of arm 5 versus arm 2 and a significant improvement of MFSI-SF in favor of arms 1, 3, and 5 versus arm 2. A significant inferiority of arm 2 versus arms 3, 4, and 5 for the primary endpoints lean body mass, REE, and MFSI-SF was observed on the basis of t test for changes., Conclusion: The interim results obtained thus far seem to suggest that the most effective treatment for cancer-related anorexia/cachexia syndrome and oxidative stress should be a combination regimen. The study is still in progress and the final results should confirm these data.

Rats offered a zinc-deficient (-Zn) diet voluntarily reduce their food intake within 3-4 days. Megestrol acetate (MA) is an appetite-stimulating drug used to treat cachexia of chronic diseases. In previous work, we found MA administration to male rats increased consumption of a -Zn diet. This approach would provide a useful tool for nutritional studies in which nutrient intake, except for zinc, would be maintained. The present study further examined the use of MA to increase consumption of a -Zn diet over a longer time period in both male and female rats. Rats were fed either a -Zn or a zinc-adequate (+Zn) diet. In Experiment 1, rats were treated orally with 0, 20, 50 or 100 mg MA/kg BW in corn oil for 21 days. MA stimulated intake of the -Zn diet in a linear manner. In Experiments 2 and 3, male and female rats, respectively, were fed the -Zn or +Zn diets and treated with 100 mg MA/kg BW for 21 days. In both experiments, MA administration increased intake of the -Zn diet to levels similar to the +Zn diet through Day 14. MA increased the hypothalamic neuropeptide Y (NPY) concentration in male rats, but did not affect serum IGF-I. MA administration improved growth of female but not male rats fed the -Zn diet. In females, serum IGF-I was not lower in zinc-deficient rats, which may have allowed the improved growth response with MA. Hence, MA administration may be a useful tool to increase consumption of a -Zn diet in short-term studies.

The interrelationships among sex hormones, caloric intake, and intermediary metabolism in health and disease are uncertain. Studies in malnourished patients with AIDS and cancer show that megestrol acetate (MA) therapy increases appetite, body weight, and body fat, while it decreases serum testosterone (T) concentration. In this study, the separate and combined effects of MA and T were investigated in 65 young adult, male, castrated, Sprague-Dawley rats who received subcutaneous implants containing placebo, MA, T, or both MA and T for 11 wk. By hierarchical multiple regression analysis, MA therapy decreased weight gain and food intake (P < 0.01), increased body fat (P = 0.024), decreased body protein (P < 0.001), and decreased the portion of calories accrued as protein rather than fat (P ratio, P < 0.03). T alone decreased fat (P < 0.03), but had no significant effect on food intake, the relative number of consumed calories utilized for growth (food efficiency), body weight, or protein. The interaction of MA and T did not affect food intake or food efficiency, but increased body weight (P < 0.02), protein (P < 0.05) and the P ratio (P < 0.02). The portion of weight gain as fat was reduced from 47.3% with MA alone to 27.4% when MA and T were combined. Thus, megestrol acetate has significant antianabolic effects that are independent of its effects upon food intake. The addition of testosterone to megestrol acetate partially antagonized MA's inhibition of lean mass accretion in these rats.

Acquired drug resistance is a major factor in the failure of doxorubicin-based chemotherapy in breast cancer. We determined the ability of megestrol acetate and/or tamoxifen to reverse doxorubicin drug resistance in a doxorubicin-resistant breast cancer line (the human MCF-7/ADR). The cytotoxicity of doxorubicin, megestrol acetate, and/or tamoxifen was determined in the sensitive and resistant cell lines utilizing the sulphorhodamine B assay. Tamoxifen alone produced an IC50 (concentration resulting in 50% inhibition of control growth) of 10.6 microM, whereas megestrol acetate alone resulted in an IC50 of 48.7 microM in the MCF-7/ADR cell line. The IC50 of doxorubicin in MCF-7/ADR was 1.9 microM. Neither megestrol acetate alone nor tamoxifen alone at 1 or 5 microM altered the IC50 of doxorubicin. However, the combination of tamoxifen (1 or 5 microM) and megestrol acetate (1 or 5 microM) synergistically sensitized MCF-7/ADR cells. Additionally, megestrol acetate and tamoxifen inhibited iodoarylazidoprazosin binding to P-glycoprotein, and, in their presence, there was an increased doxorubicin accumulation in the MCF-7/ADR cells. Furthermore, the combination of tamoxifen and megestrol acetate had much less effect on the cytotoxicity of doxorubicin in MCF-7 wild-type cells. Clinically achievable concentrations of tamoxifen and megestrol acetate can largely sensitize MCF-7/ADR to doxorubicin. The combination of these three drugs in a clinical trial may be informative.